Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode

Elkoshi, Nadav; Parikh, Shivang; Malcov-Brog, Hagar; Parikh, Roma; Manich, Paulee; Netti, Francesca; Maliah, Avishai; Elkoshi, Hana; Haj, Majd; Rippin, Ido; Frand, Jacob; Perluk, Tomer; Haiat-Factor, Rivi; Golan, Tamar; Regev-Rudzki, Neta; Kiper, Edo; Brenner, Ronen; Gonen, Pinchas; Dror, Iris; Levi, Hagai; Hameiri, Ofir; Cohen-Gulkar, Mazal; Eldar-Finkelman, Hagit; Ast, Gil; Nizri, Eran; Ziv, Yael; Elkon, Rani; Khaled, Mehdi; Ebenstein, Yuval; Shiloh, Yosef; Levy, Carmit

doi:10.1016/j.jid.2023.03.1686

Cited by 2 publications

(2 citation statements)

References 111 publications

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“…Our results also indicate that following DNA damage, the MITF interactome is dramatically remodeled. Consistent with recent observations ( Elkoshi et al 2023 ) indicating that UVB exposure reshapes the MITF interactome, we found that MITF interaction with the majority of transcription cofactors was greatly reduced on exposure to camptothecin, with the notable exception of EP300 and CREBBP, which can bind and acetylate MITF on multiple lysines ( Louphrasitthiphol et al 2020 , 2023 ). We view it as likely that the loss of interaction with transcription cofactors arises following DNA damage as a consequence of the rapid degradation of the majority of MITF that is not retained at the DNA damage sites.…”

Section: Discussionsupporting

confidence: 92%

DNA damage remodels the MITF interactome to increase melanoma genomic instability

Binet,

Lambert,

Tomkova

et al. 2024

Genes Dev.

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Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Using melanoma as a model, we show here that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a nontranscriptional role in shaping the DDR. On exposure to DNA-damaging agents, MITF is phosphorylated at S325, and its interactome is dramatically remodeled; most transcription cofactors dissociate, and instead MITF interacts with the MRE11–RAD50–NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement with this, high MITF levels are associated with increased single-nucleotide and copy number variant burdens in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of DNA-PKcs-phosphorylated MITF. Our data suggest that a nontranscriptional function of a lineage-restricted transcription factor contributes to a tissue-specialized modulation of the DDR that can impact cancer initiation.

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Section: Discussionsupporting

confidence: 92%

DNA damage remodels the MITF interactome to increase melanoma genomic instability

Binet,

Lambert,

Tomkova

et al. 2024

Genes Dev.

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“…63 UV radiation not only plays a crucial role in vitamin D synthesis and immune regulation but also in DNA damage, leading to skin cancer through mechanisms like the mitogen-activated protein kinase (MAPK) signaling pathway and immune system suppression. 64,65 The complex interplay of UV exposure, immune suppression, genetic mutations, and viral oncogenesis underscores the multifaceted nature of skin cancer development. [66][67][68][69] CUR exhibits remarkable anti-cancer properties by selectively targeting tumor cells while sparing normal ones.…”

Section: Skin Cancermentioning

confidence: 99%

Advancements in Dermatological Applications of Curcumin: Clinical Efficacy and Mechanistic Insights in the Management of Skin Disorders

Mo,

Yuan,

Guan

et al. 2024

CCID

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Curcumin, derived from Curcuma longa (turmeric), exhibits significant potential in dermatology, addressing conditions like atopic dermatitis, psoriasis, chronic wounds, skin cancer, and infections through its anti-inflammatory, antioxidant, anticancer, and antimicrobial properties. This review synthesizes evidence on curcumin's mechanisms, including modulation of immune responses and promotion of wound healing, showcasing its efficacy in reducing inflammation, cytokine levels, and enhancing skin barrier functions. Studies highlight curcumin's ability to selectively target tumor cells, suggesting a multifaceted approach to cancer therapy with minimal side effects. Despite promising therapeutic benefits, challenges remain in bioavailability, potency, and targeted delivery, underscoring the need for further research to optimize dosages, delivery methods, and assess long-term safety. The integration of curcumin into dermatological practice requires a balanced consideration of evidence-based efficacy and safety. Curcumin's comprehensive utility in dermatology, coupled with the necessity for advanced scientific exploration, emphasizes the importance of combining traditional knowledge with contemporary research to improve patient care in dermatology. This approach could significantly enhance outcomes for individuals with skin-related conditions, marking curcumin as a versatile and promising agent in the field.

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Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode

Cited by 2 publications

References 111 publications

DNA damage remodels the MITF interactome to increase melanoma genomic instability

DNA damage remodels the MITF interactome to increase melanoma genomic instability

Advancements in Dermatological Applications of Curcumin: Clinical Efficacy and Mechanistic Insights in the Management of Skin Disorders

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