UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma.
Wolf Yochai,Bartok Osnat,Patkar Sushant,Eli Gitit Bar,Cohen Sapir,Litchfield Kevin,Levy Ronen,Jiménez-Sánchez Alejandro,Trabish Sophie,Lee Joo Sang,Karathia Hiren,Barnea Eilon,Day Chi-Ping,Cinnamon Einat,Stein Ilan,Solomon Adam,Bitton Lital,Pérez-Guijarro Eva,Dubovik Tania,Shen-Orr Shai S,Miller Martin L,Merlino Glenn,Levin Yishai,Pikarsky Eli,Eisenbach Lea,Admon Arie,Swanton Charles,Ruppin Eytan,Samuels Yardena
Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade.
A conserved motif in JNK/p38-specific MAPK phosphatases as a determinant for JNK1 recognition and inactivation.
Liu Xin,Zhang Chen-Song,Lu Chang,Lin Sheng-Cai,Wu Jia-Wei,Wang Zhi-Xin
Mitogen-activated protein kinases (MAPKs), important in a large array of signalling pathways, are tightly controlled by a cascade of protein kinases and by MAPK phosphatases (MKPs). MAPK signalling efficiency and specificity is modulated by protein-protein interactions between individual MAPKs and the docking motifs in cognate binding partners. Two types of docking interactions have been identified: D-motif-mediated interaction and FXF-docking interaction. Here we report the crystal structure of JNK1 bound to the catalytic domain of MKP7 at 2.4-Å resolution, providing high-resolution structural insight into the FXF-docking interaction. The (285)FNFL(288) segment in MKP7 directly binds to a hydrophobic site on JNK1 that is near the MAPK insertion and helix αG. Biochemical studies further reveal that this highly conserved structural motif is present in all members of the MKP family, and the interaction mode is universal and critical for the MKP-MAPK recognition and biological function.
Optical control of protein phosphatase function.
Courtney Taylor M,Deiters Alexander
Protein phosphatases are involved in embryonic development, metabolic homeostasis, stress response, cell cycle transitions, and many other essential biological mechanisms. Unlike kinases, protein phosphatases remain understudied and less characterized. Traditional genetic and biochemical methods have contributed significantly to our understanding; however, these methodologies lack precise and acute spatiotemporal control. Here, we report the development of a light-activated protein phosphatase, the dual specificity phosphatase 6 (DUSP6 or MKP3). Through genetic code expansion, MKP3 is placed under optical control via two different approaches: (i) incorporation of a caged cysteine into the active site for controlling catalytic activity and (ii) incorporation of a caged lysine into the kinase interaction motif for controlling the protein-protein interaction between the phosphatase and its substrate. Both strategies are expected to be applicable to the engineering of a wide range of light-activated phosphatases. Applying the optogenetically controlled MKP3 in conjunction with live cell reporters, we discover that ERK nuclear translocation is regulated in a graded manner in response to increasing MKP3 activity.
Direct infant UV light exposure is associated with eczema and immune development.
Rueter Kristina,Jones Anderson P,Siafarikas Aris,Lim Ee-Mun,Bear Natasha,Noakes Paul S,Prescott Susan L,Palmer Debra J
The Journal of allergy and clinical immunology
BACKGROUND:Suboptimal vitamin D levels during critical periods of immune development have emerged as an explanation for higher rates of allergic diseases associated with industrialization and residing at higher latitudes. OBJECTIVE:We sought to determine the effects of early postnatal vitamin D supplementation on infant eczema and immune development. METHODS:By using a double-blind randomized controlled trial, newborn infants were randomized to receive vitamin D supplementation (400 IU/d) or a placebo until 6 months of age. Some infants also wore personal UV dosimeters to measure direct UV light (290-380 nm) exposure. Infant vitamin D levels were measured at 3 and 6 months of age. Eczema, wheeze, and immune function outcomes were assessed at 6 months of age. RESULTS:At 3 (P < .01) and 6 (P = .02) months of age, vitamin D levels were greater for the vitamin D-supplemented group than the placebo group, but there was no difference in eczema incidence between groups. Infants with eczema were found to have had less UV light exposure (median, 555 Joules per square meter [J/m; interquartile range, 322-1210 J/m]) compared with those without eczema (median, 998 J/m [interquartile range, 676-1577 J/m]; P = .02). UV light exposure was also inversely correlated with IL-2, GM-CSF, and eotaxin production to Toll-like receptor ligands. CONCLUSION:This study is the first to demonstrate an association between greater direct UV light exposures in early infancy with lower incidence of eczema and proinflammatory immune markers by 6 months of age. Our findings indicate that UV light exposure appears more beneficial than vitamin D supplementation as an allergy prevention strategy in early life.
Advances in atopic dermatitis in 2015.
Nomura Takashi,Kabashima Kenji
The Journal of allergy and clinical immunology
This review aims to highlight recently published articles on atopic dermatitis (AD). Updated are the insights into epidemiology, pathology, diagnostics, and therapy. Epidemiologic studies have revealed a positive correlation between AD and systemic conditions, such as rheumatoid arthritis, inflammatory bowel disease, and neonatal adiposity. Pathologic findings highlight the involvement of novel barrier factors (desmoplakin and claudin), novel immune cell subsets (pathogenic effector T2 cells and group 2 innate lymphoid cells), and differential skewing of helper T cells (eg, T17 dominance in Asians with AD). As diagnostics, noninvasive examinations of the transepidermal water loss of neonates, the density of epidermal Staphylococcus species, and the gut flora might prognosticate the onset of AD. As for therapy, various methods are proposed, including conventional (petrolatum and UV) and molecule-oriented regimens targeting Janus kinase, signal transducer and activator of transcription 3, extracellular signal-regulated kinase, sirtuin 1, or aryl hydrocarbon receptor.
Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β.
Mohammed Javed,Beura Lalit K,Bobr Aleh,Astry Brian,Chicoine Brian,Kashem Sakeen W,Welty Nathan E,Igyártó Botond Z,Wijeyesinghe Sathi,Thompson Emily A,Matte Catherine,Bartholin Laurent,Kaplan Alesia,Sheppard Dean,Bridges Alina G,Shlomchik Warren D,Masopust David,Kaplan Daniel H
Cells of the immune system that reside in barrier epithelia provide a first line of defense against pathogens. Langerhans cells (LCs) and CD8(+) tissue-resident memory T cells (TRM cells) require active transforming growth factor-β1 (TGF-β) for epidermal residence. Here we found that integrins αvβ6 and αvβ8 were expressed in non-overlapping patterns by keratinocytes (KCs) and maintained the epidermal residence of LCs and TRM cells by activating latent TGF-β. Similarly, the residence of dendritic cells and TRM cells in the small intestine epithelium also required αvβ6. Treatment of the skin with ultraviolet irradiation decreased integrin expression on KCs and reduced the availability of active TGF-β, which resulted in LC migration. Our data demonstrated that regulated activation of TGF-β by stromal cells was able to directly control epithelial residence of cells of the immune system through a novel mechanism of intercellular communication.
From melanocytes to melanomas.
Shain A Hunter,Bastian Boris C
Nature reviews. Cancer
Melanomas on sun-exposed skin are heterogeneous tumours, which can be subtyped on the basis of their cumulative levels of exposure to ultraviolet (UV) radiation. A melanocytic neoplasm can also be staged by how far it has progressed, ranging from a benign neoplasm, such as a naevus, to a malignant neoplasm, such as a metastatic melanoma. Each subtype of melanoma can evolve through distinct evolutionary trajectories, passing through (or sometimes skipping over) various stages of transformation. This Review delineates several of the more common progression trajectories that occur in the patient setting and proposes models for tumour evolution that integrate genetic, histopathological, clinical and biological insights from the melanoma literature.
Molecular machines open cell membranes.
García-López Víctor,Chen Fang,Nilewski Lizanne G,Duret Guillaume,Aliyan Amir,Kolomeisky Anatoly B,Robinson Jacob T,Wang Gufeng,Pal Robert,Tour James M
Beyond the more common chemical delivery strategies, several physical techniques are used to open the lipid bilayers of cellular membranes. These include using electric and magnetic fields, temperature, ultrasound or light to introduce compounds into cells, to release molecular species from cells or to selectively induce programmed cell death (apoptosis) or uncontrolled cell death (necrosis). More recently, molecular motors and switches that can change their conformation in a controlled manner in response to external stimuli have been used to produce mechanical actions on tissue for biomedical applications. Here we show that molecular machines can drill through cellular bilayers using their molecular-scale actuation, specifically nanomechanical action. Upon physical adsorption of the molecular motors onto lipid bilayers and subsequent activation of the motors using ultraviolet light, holes are drilled in the cell membranes. We designed molecular motors and complementary experimental protocols that use nanomechanical action to induce the diffusion of chemical species out of synthetic vesicles, to enhance the diffusion of traceable molecular machines into and within live cells, to induce necrosis and to introduce chemical species into live cells. We also show that, by using molecular machines that bear short peptide addends, nanomechanical action can selectively target specific cell-surface recognition sites. Beyond the in vitro applications demonstrated here, we expect that molecular machines could also be used in vivo, especially as their design progresses to allow two-photon, near-infrared and radio-frequency activation.
UV Irradiation Induces a Non-coding RNA that Functionally Opposes the Protein Encoded by the Same Gene.
Williamson Laura,Saponaro Marco,Boeing Stefan,East Philip,Mitter Richard,Kantidakis Theodoros,Kelly Gavin P,Lobley Anna,Walker Jane,Spencer-Dene Bradley,Howell Michael,Stewart Aengus,Svejstrup Jesper Q
The transcription-related DNA damage response was analyzed on a genome-wide scale with great spatial and temporal resolution. Upon UV irradiation, a slowdown of transcript elongation and restriction of gene activity to the promoter-proximal ∼25 kb is observed. This is associated with a shift from expression of long mRNAs to shorter isoforms, incorporating alternative last exons (ALEs) that are more proximal to the transcription start site. Notably, this includes a shift from a protein-coding ASCC3 mRNA to a shorter ALE isoform of which the RNA, rather than an encoded protein, is critical for the eventual recovery of transcription. The non-coding ASCC3 isoform counteracts the function of the protein-coding isoform, indicating crosstalk between them. Thus, the ASCC3 gene expresses both coding and non-coding transcript isoforms with opposite effects on transcription recovery after UV-induced DNA damage.
Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma.
North Jeffrey P,Golovato Justin,Vaske Charles J,Sanborn J Zachary,Nguyen Andrew,Wu Wei,Goode Benjamin,Stevers Meredith,McMullen Kevin,Perez White Bethany E,Collisson Eric A,Bloomer Michele,Solomon David A,Benz Stephen C,Cho Raymond J
Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.
Moderate UV Exposure Enhances Learning and Memory by Promoting a Novel Glutamate Biosynthetic Pathway in the Brain.
Zhu Hongying,Wang Ning,Yao Lei,Chen Qi,Zhang Ran,Qian Junchao,Hou Yiwen,Guo Weiwei,Fan Sijia,Liu Siling,Zhao Qiaoyun,Du Feng,Zuo Xin,Guo Yujun,Xu Yan,Li Jiali,Xue Tian,Zhong Kai,Song Xiaoyuan,Huang Guangming,Xiong Wei
Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes.
Systemic lupus erythematosus.
Kaul Arvind,Gordon Caroline,Crow Mary K,Touma Zahi,Urowitz Murray B,van Vollenhoven Ronald,Ruiz-Irastorza Guillermo,Hughes Graham
Nature reviews. Disease primers
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.
State of the science on prevention and screening to reduce melanoma incidence and mortality: The time is now.
Tripp Mary K,Watson Meg,Balk Sophie J,Swetter Susan M,Gershenwald Jeffrey E
CA: a cancer journal for clinicians
Answer questions and earn CME/CNE Although overall cancer incidence rates are decreasing, melanoma incidence rates continue to increase about 3% annually. Melanoma is a significant public health problem that exacts a substantial financial burden. Years of potential life lost from melanoma deaths contribute to the social, economic, and human toll of this disease. However, most cases are potentially preventable. Research has clearly established that exposure to ultraviolet radiation increases melanoma risk. Unprecedented antitumor activity and evolving survival benefit from novel targeted therapies and immunotherapies are now available for patients with unresectable and/or metastatic melanoma. Still, prevention (minimizing sun exposure that may result in tanned or sunburned skin and avoiding indoor tanning) and early detection (identifying lesions before they become invasive or at an earlier stage) have significant potential to reduce melanoma incidence and melanoma-associated deaths. This article reviews the state of the science on prevention and early detection of melanoma and current areas of scientific uncertainty and ongoing debate. The US Surgeon General's Call to Action to Prevent Skin Cancer and US Preventive Services Task Force reviews on skin cancer have propelled a national discussion on melanoma prevention and screening that makes this an extraordinary and exciting time for diverse disciplines in multiple sectors-health care, government, education, business, advocacy, and community-to coordinate efforts and leverage existing knowledge to make major strides in reducing the public health burden of melanoma in the United States. CA Cancer J Clin 2016;66:460-480. © 2016 American Cancer Society.
Steroid Hormone Vitamin D: Implications for Cardiovascular Disease.
Demer Linda L,Hsu Jeffrey J,Tintut Yin
Understanding of vitamin D physiology is important because about half of the population is being diagnosed with deficiency and treated with supplements. Clinical guidelines were developed based on observational studies showing an association between low serum levels and increased cardiovascular risk. However, new randomized controlled trials have failed to confirm any cardiovascular benefit from supplementation in the general population. A major concern is that excess vitamin D is known to cause calcific vasculopathy and valvulopathy in animal models. For decades, administration of vitamin D has been used in rodents as a reliable experimental model of vascular calcification. Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases. As a fat-soluble hormone, the vitamin D-hormone metabolites must have special mechanisms for delivery in the aqueous bloodstream. Importantly, endogenously synthesized forms are carried by a binding protein, whereas dietary forms are carried within lipoprotein particles. This may result in distinct biodistributions for sunlight-derived versus supplement-derived vitamin D hormones. Because the cardiovascular effects of vitamin D hormones are not straightforward, both toxic and beneficial effects may result from current recommendations.
Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis.
Ma Xiaolu,Liu Hongmei,Li Jing,Wang Yihao,Ding Yue-He,Shen Hongyan,Yang Yeran,Sun Chenyi,Huang Min,Tu Yingfeng,Liu Yang,Zhao Yongliang,Dong Meng-Qiu,Xu Ping,Tang Tie-Shan,Guo Caixia
DNA polymerase η (Polη) facilitates translesion DNA synthesis (TLS) across ultraviolet (UV) irradiation- and cisplatin-induced DNA lesions implicated in skin carcinogenesis and chemoresistant phenotype formation, respectively. However, whether post-translational modifications of Polη are involved in these processes remains largely unknown. Here, we reported that human Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase upon DNA damage. Abrogation of this modification results in a reduced level of CRL4-dependent Polη polyubiquitination at lysine 462, a delayed p97-dependent removal of Polη from replication forks, and significantly enhanced UV-induced mutagenesis even though Polη focus formation and its efficacy to bypass across cyclobutane pyrimidine dimers after UV irradiation are not affected. Furthermore, the O-GlcNAc-deficient T457A mutation impairs TLS to bypass across cisplatin-induced lesions, causing increased cellular sensitivity to cisplatin. Our findings demonstrate a novel role of Polη O-GlcNAcylation in TLS regulation and genome stability maintenance and establish a new rationale to improve chemotherapeutic treatment.
The protective role of DOT1L in UV-induced melanomagenesis.
Zhu Bo,Chen Shuyang,Wang Hongshen,Yin Chengqian,Han Changpeng,Peng Cong,Liu Zhaoqian,Wan Lixin,Zhang Xiaoyang,Zhang Jie,Lian Christine G,Ma Peilin,Xu Zhi-Xiang,Prince Sharon,Wang Tao,Gao Xiumei,Shi Yujiang,Liu Dali,Liu Min,Wei Wenyi,Wei Zhi,Pan Jingxuan,Wang Yongjun,Xuan Zhenyu,Hess Jay,Hayward Nicholas K,Goding Colin R,Chen Xiang,Zhou Jun,Cui Rutao
The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis.
Understanding the connection between platelet-activating factor, a UV-induced lipid mediator of inflammation, immune suppression and skin cancer.
Damiani Elisabetta,Ullrich Stephen E
Progress in lipid research
Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome.
Linking Protein and RNA Function within the Same Gene.
Szempruch Anthony,Guttman Mitchell
Exposure to ultraviolet light leads to a cell-wide DNA damage response that includes a global reduction in transcription. Williamson et al., identify a protein involved in this process as well as a noncoding RNA produced by alternative processing of RNA transcribed from the same gene that promotes recovery from the repressed state.
Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH.
Mazouzi Abdelghani,Battistini Federica,Moser Sarah C,Ferreira da Silva Joana,Wiedner Marc,Owusu Michel,Lardeau Charles-Hugues,Ringler Anna,Weil Beatrix,Neesen Jürgen,Orozco Modesto,Kubicek Stefan,Loizou Joanna I
DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available. Here we performed a high-throughput chemical screen for agents that could alleviate the cellular sensitivity of NER-deficient cells to UV-induced DNA damage. This led to the identification of the clinically approved anti-diabetic drug acetohexamide, which promoted clearance of UV-induced DNA damage without the accumulation of chromosomal aberrations, hence promoting cellular survival. Acetohexamide exerted this protective function by antagonizing expression of the DNA glycosylase, MUTYH. Together, our data reveal the existence of an NER-independent mechanism to remove UV-induced DNA damage and prevent cell death.
p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage.
Borisova Marina E,Voigt Andrea,Tollenaere Maxim A X,Sahu Sanjeeb Kumar,Juretschke Thomas,Kreim Nastasja,Mailand Niels,Choudhary Chunaram,Bekker-Jensen Simon,Akutsu Masato,Wagner Sebastian A,Beli Petra
Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV-light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here we employ quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA-binding proteins as primary substrates and 14-3-3 as direct readers of p38-MK2-dependent phosphorylation induced by UV light. Mechanistically, we show that MK2 phosphorylates the RNA-binding subunit of the NELF complex NELFE on Serine 115. NELFE phosphorylation promotes the recruitment of 14-3-3 and rapid dissociation of the NELF complex from chromatin, which is accompanied by RNA polymerase II elongation.
Genome-wide excision repair in Arabidopsis is coupled to transcription and reflects circadian gene expression patterns.
Oztas Onur,Selby Christopher P,Sancar Aziz,Adebali Ogun
Plants are exposed to numerous DNA-damaging stresses including the exposure to ultraviolet (UV) component of solar radiation. They employ nucleotide excision repair to remove DNA-bulky adducts and to help eliminate UV-induced DNA lesions, so as to maintain their genome integrity and their fitness. Here, we generated genome-wide single-nucleotide resolution excision repair maps of UV-induced DNA damage in Arabidopsis at different circadian time points. Our data show that the repair of UV lesions for a large fraction of the genome is controlled by the joint actions of the circadian clock and transcription by RNA polymerase II. Our findings reveal very strong repair preference for the transcribed strands of active genes in Arabidopsis, and 10-30% of the transcription-coupled repair is circadian time-dependent. This dynamic range in nucleotide excision repair levels throughout the day enables Arabidopsis to cope with the bulky DNA lesion-inducing environmental factors including UV.
Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.
Sarkar Mrinal K,Hile Grace A,Tsoi Lam C,Xing Xianying,Liu Jianhua,Liang Yun,Berthier Celine C,Swindell William R,Patrick Matthew T,Shao Shuai,Tsou Pei-Suen,Uppala Ranjitha,Beamer Maria A,Srivastava Anshika,Bielas Stephanie L,Harms Paul W,Getsios Spiro,Elder James T,Voorhees John J,Gudjonsson Johann E,Kahlenberg J Michelle
Annals of the rheumatic diseases
OBJECTIVE:Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin. METHODS:mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. RESULTS: is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis. CONCLUSION:Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.
UV-Protection Timer Controls Linkage between Stress and Pigmentation Skin Protection Systems.
Malcov-Brog Hagar,Alpert Ayelet,Golan Tamar,Parikh Shivang,Nordlinger Alice,Netti Francesca,Sheinboim Danna,Dror Iris,Thomas Laetitia,Cosson Camille,Gonen Pinchas,Stanevsky Yury,Brenner Ronen,Perluk Tomer,Frand Jacob,Elgavish Sharona,Nevo Yuval,Rahat Dolev,Tabach Yuval,Khaled Mehdi,Shen-Orr Shai S,Levy Carmit
Skin sun exposure induces two protection programs: stress responses and pigmentation, the former within minutes and the latter only hours afterward. Although serving the same physiological purpose, it is not known whether and how these programs are coordinated. Here, we report that UVB exposure every other day induces significantly more skin pigmentation than the higher frequency of daily exposure, without an associated increase in stress responses. Using mathematical modeling and empirical studies, we show that the melanocyte master regulator, MITF, serves to synchronize stress responses and pigmentation and, furthermore, functions as a UV-protection timer via damped oscillatory dynamics, thereby conferring a trade-off between the two programs. MITF oscillations are controlled by multiple negative regulatory loops, one at the transcriptional level involving HIF1α and another post-transcriptional loop involving microRNA-148a. These findings support trait linkage between the two skin protection programs, which, we speculate, arose during furless skin evolution to minimize skin damage.
Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution.
Shain A Hunter,Joseph Nancy M,Yu Richard,Benhamida Jamal,Liu Shanshan,Prow Tarl,Ruben Beth,North Jeffrey,Pincus Laura,Yeh Iwei,Judson Robert,Bastian Boris C
We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.
Insight into immunocytes infiltrations in polymorphous light eruption.
Lei Dongyun,Wu Wenjuan,Yang Li,Li Yan,Feng Jiaqi,Lyu Lechun,He Li
Polymorphous light eruption (PLE) which is one of the most common photodermatoses has been demonstrated to be immune-mediated disorder. Resistance to UV-induced immunosuppression resulting from differential immune cells infiltration and cytokines secretion has been highlighted in the pathogenesis of PLE. In this study, we reviewed differential patterns of immune cells infiltrations and cytokines secretion that may contribute to PLE occurrence and development.
Melanoma: a global perspective.
Ossio Raul,Roldán-Marín Rodrigo,Martínez-Said Héctor,Adams David J,Robles-Espinoza Carla Daniela
Nature reviews. Cancer
Most of our current knowledge of melanoma is derived from the study of patients from populations of European descent, for whom public health, sun protection initiatives and screening measures have appreciably decreased disease mortality. Notably, some melanoma subtypes that most commonly develop in other populations are not associated with exposure to ultraviolet (UV) light, suggesting a different disease aetiology. Further study of these subtypes is necessary to understand their risk factors and genomic architecture, and to tailor therapies and public health campaigns to benefit patients of all ethnic groups.
Photoprotection: extending lessons learned from studying natural sunscreens to the design of artificial sunscreen constituents.
Baker Lewis A,Marchetti Barbara,Karsili Tolga N V,Stavros Vasilios G,Ashfold Michael N R
Chemical Society reviews
Evolution has ensured that plants and animals have developed effective protection mechanisms against the potentially harmful effects of incident ultraviolet radiation (UVR). Tanning is one such mechanism in humans, but tanning only occurs post-exposure to UVR. Hence, there is ever growing use of commercial sunscreens to pre-empt overexposure to UVR. Key requirements for any chemical filter molecule used in such a photoprotective capacity include a large absorption cross-section in the UV-A and UV-B spectral regions and the availability of one or more mechanisms whereby the absorbed photon energy can be dissipated without loss of the molecular integrity of the chemical filter. Here we summarise recent experimental (mostly ultrafast pump-probe spectroscopy studies) and computational progress towards unravelling various excited state decay mechanisms that afford the necessary photostability in chemical filters found in nature and those used in commercial sunscreens. We also outline ways in which a better understanding of the photophysics and photochemistry of sunscreen molecules selected by nature could aid the design of new and improved commercial sunscreen formulations.
A commensal strain of protects against skin neoplasia.
Nakatsuji Teruaki,Chen Tiffany H,Butcher Anna M,Trzoss Lynnie L,Nam Sang-Jip,Shirakawa Karina T,Zhou Wei,Oh Julia,Otto Michael,Fenical William,Gallo Richard L
We report the discovery that strains of produce 6--hydroxyaminopurine (6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control strain that did not produce 6-HAP. strains producing 6-HAP were found in the metagenome from multiple healthy human subjects, suggesting that the microbiome of some individuals may confer protection against skin cancer. These findings show a new role for skin commensal bacteria in host defense.
The biology and treatment of Merkel cell carcinoma: current understanding and research priorities.
Harms Paul W,Harms Kelly L,Moore Patrick S,DeCaprio James A,Nghiem Paul,Wong Michael K K,Brownell Isaac,
Nature reviews. Clinical oncology
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy. Despite these rapid advances in the understanding and management of patients with MCC, many basic, translational and clinical research questions remain unanswered. In March 2018, an International Workshop on Merkel Cell Carcinoma Research was held at the US National Cancer Institute, at which academic, government and industry experts met to identify the highest-priority research questions. Here, we review the biology and treatment of MCC and report the consensus-based recommendations agreed upon during the workshop.
A protective Langerhans cell-keratinocyte axis that is dysfunctional in photosensitivity.
Shipman William D,Chyou Susan,Ramanathan Anusha,Izmirly Peter M,Sharma Sneh,Pannellini Tania,Dasoveanu Dragos C,Qing Xiaoping,Magro Cynthia M,Granstein Richard D,Lowes Michelle A,Pamer Eric G,Kaplan Daniel H,Salmon Jane E,Mehrara Babak J,Young James W,Clancy Robert M,Blobel Carl P,Lu Theresa T
Science translational medicine
Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.
Melanocyte Stem Cell Activation and Translocation Initiate Cutaneous Melanoma in Response to UV Exposure.
Moon Hyeongsun,Donahue Leanne R,Choi Eunju,Scumpia Philip O,Lowry William E,Grenier Jennifer K,Zhu Jerry,White Andrew C
Cell stem cell
Melanoma is one of the deadliest cancers, yet the cells of origin and mechanisms of tumor initiation remain unclear. The majority of melanomas emerge from clear skin without a precursor lesion, but it is unknown whether these melanomas can arise from melanocyte stem cells (MCSCs). Here we employ mouse models to define the role of MCSCs as melanoma cells of origin, demonstrate that MCSC quiescence acts as a tumor suppressor, and identify the extrinsic environmental and molecular factors required for the critical early steps of melanoma initiation. Specifically, melanomas originate from melanoma-competent MCSCs upon stimulation by UVB, which induces MCSC activation and translocation via an inflammation-dependent process. Moreover, the chromatin-remodeling factor Hmga2 in the skin plays a critical role in UVB-mediated melanomagenesis. These findings delineate melanoma formation from melanoma-competent MCSCs following extrinsic stimuli, and they suggest that abrogation of Hmga2 function in the microenvironment can suppress MCSC-originating cutaneous melanomas.
Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.
Murai Kasumi,Skrupskelyte Greta,Piedrafita Gabriel,Hall Michael,Kostiou Vasiliki,Ong Swee Hoe,Nagy Tibor,Cagan Alex,Goulding David,Klein Allon M,Hall Benjamin A,Jones Philip H
Cell stem cell
Aging human tissues, such as sun-exposed epidermis, accumulate a high burden of progenitor cells that carry oncogenic mutations. However, most progenitors carrying such mutations colonize and persist in normal tissue without forming tumors. Here, we investigated tissue-level constraints on clonal progenitor behavior by inducing a single-allele p53 mutation (Trp53; p53), prevalent in normal human epidermis and squamous cell carcinoma, in transgenic mouse epidermis. p53 progenitors initially outcompeted wild-type cells due to enhanced proliferation, but subsequently reverted toward normal dynamics and homeostasis. Physiological doses of UV light accelerated short-term expansion of p53 clones, but their frequency decreased with protracted irradiation, possibly due to displacement by UV-induced mutant clones with higher competitive fitness. These results suggest multiple mechanisms restrain the proliferation of p53 progenitors, thereby maintaining epidermal integrity.
Merkel cell carcinoma.
Becker Jürgen C,Stang Andreas,DeCaprio James A,Cerroni Lorenzo,Lebbé Celeste,Veness Michael,Nghiem Paul
Nature reviews. Disease primers
Merkel cell carcinoma (MCC) is a rare but highly aggressive skin cancer with neuroendocrine features. MCC pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. The two aetiologies share similar clinical, histopathological and prognostic characteristics. MCC presents with a solitary cutaneous or subcutaneous nodule, most frequently in sun-exposed areas. In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. Confirmation of diagnosis relies on analyses of histological features and immunological marker expression profiles of the lesion. At primary diagnosis, loco-regional metastases are already present in ∼30% of patients. Excision of the tumour is the first-line therapy; if not feasible, radiotherapy can often effectively control the disease. Chemotherapy was the only alternative in advanced-stage or refractory MCC until several clinical trials demonstrated the efficacy of immune-checkpoint inhibitors.
Efficient Angiogenesis-Based Diabetic Wound Healing/Skin Reconstruction through Bioactive Antibacterial Adhesive Ultraviolet Shielding Nanodressing with Exosome Release.
Wang Min,Wang Chenggui,Chen Mi,Xi Yuewei,Cheng Wei,Mao Cong,Xu Tianzhen,Zhang Xingxing,Lin Cai,Gao Weiyang,Guo Yi,Lei Bo
Diabetic wound healing and angiogenesis remain a worldwide challenge for both clinic and research. The use of adipose stromal cell derived exosomes delivered by bioactive dressing provides a potential strategy for repairing diabetic wounds with less scar formation and fast healing. In this study, we fabricated an injectable adhesive thermosensitive multifunctional polysaccharide-based dressing (FEP) with sustained pH-responsive exosome release for promoting angiogenesis and diabetic wound healing. The FEP dressing possessed multifunctional properties including efficient antibacterial activity/multidrug-resistant bacteria, fast hemostatic ability, self-healing behavior, and tissue-adhesive and good UV-shielding performance. FEP@exosomes (FEP@exo) can significantly enhance the proliferation, migration, and tube formation of endothelial cells . results from a diabetic full-thickness cutaneous wound model showed that FEP@exo dressing accelerated the wound healing by stimulating the angiogenesis process of the wound tissue. The enhanced cell proliferation, granulation tissue formation, collagen deposition, remodeling, and re-epithelialization probably lead to the fast healing with less scar tissue formation and skin appendage regeneration. This study showed that combining bioactive molecules into multifunctional dressing should have great potential in achieving satisfactory healing in diabetic and other vascular-impaired related wounds.
Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma.
Trucco Lucas D,Mundra Piyushkumar A,Hogan Kate,Garcia-Martinez Pablo,Viros Amaya,Mandal Amit K,Macagno Nicolas,Gaudy-Marqueste Caroline,Allan Donald,Baenke Franziska,Cook Martin,McManus Clare,Sanchez-Laorden Berta,Dhomen Nathalie,Marais Richard
The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.
Melatonin and its derivatives counteract the ultraviolet B radiation-induced damage in human and porcine skin ex vivo.
Skobowiat Cezary,Brożyna Anna A,Janjetovic Zorica,Jeayeng Saowanee,Oak Allen S W,Kim Tae-Kang,Panich Uraiwan,Reiter Russel J,Slominski Andrzej T
Journal of pineal research
Melatonin and its derivatives (N -acetyl-N -formyl-5-methoxykynurenine [AFMK] and N-acetyl serotonin [NAS]) have broad-spectrum protective effects against photocarcinogenesis, including both direct and indirect antioxidative actions, regulation of apoptosis and DNA damage repair; these data were primarily derived from in vitro models. This study evaluates possible beneficial effects of melatonin and its active derivatives against ultraviolet B (UVB)-induced harm to human and porcine skin ex vivo and to cultured HaCaT cells. The topical application of melatonin, AFMK, or NAS protected epidermal cells against UVB-induced 8-OHdG formation and apoptosis with a further increase in p53 expression, especially after application of melatonin or AFMK but not after NAS use. The photoprotective action was observed in pre- and post-UVB treatment in both human and porcine models. Melatonin along with its derivatives upregulated also the expression of antioxidative enzymes after UVB radiation of HaCaT cells. The exogenous application of melatonin or its derivatives represents a potent and promising tool for preventing UVB-induced oxidative stress and DNA damage. This protection results in improved genomic, cellular, and tissue integrity against UVB-induced carcinogenesis, especially when applied prior to UV exposure. In addition, our ex vivo experiments provide fundamental justification for further testing the clinical utility of melatonin and metabolites as protectors again UVB in human subjects. Our ex vivo data constitute the bridge between vitro to vivo translation and thus justifies the pursue for further clinical utility of melatonin in maintaining skin homeostasis.
Exposure to Ultraviolet Radiation in the Modulation of Human Diseases.
Hart Prue H,Norval Mary,Byrne Scott N,Rhodes Lesley E
Annual review of pathology
This review focuses primarily on the beneficial effects for human health of exposure to ultraviolet radiation (UVR). UVR stimulates anti-inflammatory and immunosuppressive pathways in skin that modulate psoriasis, atopic dermatitis, and vitiligo; suppresses cutaneous lesions of graft-versus-host disease; and regulates some infection and vaccination outcomes. While polymorphic light eruption and the cutaneous photosensitivity of systemic lupus erythematosus are triggered by UVR, polymorphic light eruption also frequently benefits from UVR-induced immunomodulation. For systemic diseases such as multiple sclerosis, type 1 diabetes, asthma, schizophrenia, autism, and cardiovascular disease, any positive consequences of UVR exposure are more speculative, but could occur through the actions of UVR-induced regulatory cells and mediators, including 1,25-dihydroxy vitamin D, interleukin-10, and nitric oxide. Reduced UVR exposure is a risk factor for the development of several inflammatory, allergic, and autoimmune conditions, including diseases initiated in early life. This suggests that UVR-induced molecules can regulate cell maturation in developing organs.