TY - JOUR
T1 - Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode
AU - Elkoshi, Nadav
AU - Parikh, Shivang
AU - Malcov-Brog, Hagar
AU - Parikh, Roma
AU - Manich, Paulee
AU - Netti, Francesca
AU - Maliah, Avishai
AU - Elkoshi, Hana
AU - Haj, Majd
AU - Rippin, Ido
AU - Frand, Jacob
AU - Perluk, Tomer
AU - Haiat-Factor, Rivi
AU - Golan, Tamar
AU - Regev-Rudzki, Neta
AU - Kiper, Edo
AU - Brenner, Ronen
AU - Gonen, Pinchas
AU - Dror, Iris
AU - Levi, Hagai
AU - Hameiri, Ofir
AU - Cohen-Gulkar, Mazal
AU - Eldar-Finkelman, Hagit
AU - Ast, Gil
AU - Nizri, Eran
AU - Ziv, Yael
AU - Elkon, Rani
AU - Khaled, Mehdi
AU - Ebenstein, Yuval
AU - Shiloh, Yosef
AU - Levy, Carmit
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/12
Y1 - 2023/12
N2 - Skin pigmentation is paused after sun exposure; however, the mechanism behind this pausing is unknown. In this study, we found that the UVB-induced DNA repair system, led by the ataxia telangiectasia mutated (ATM) protein kinase, represses MITF transcriptional activity of pigmentation genes while placing MITF in DNA repair mode, thus directly inhibiting pigment production. Phosphoproteomics analysis revealed ATM to be the most significantly enriched pathway among all UVB-induced DNA repair systems. ATM inhibition in mouse or human skin, either genetically or chemically, induces pigmentation. Upon UVB exposure, MITF transcriptional activation is blocked owing to ATM-dependent phosphorylation of MITF on S414, which modifies MITF activity and interactome toward DNA repair, including binding to TRIM28 and RBBP4. Accordingly, MITF genome occupancy is enriched in sites of high DNA damage that are likely repaired. This suggests that ATM harnesses the pigmentation key activator for the necessary rapid, efficient DNA repair, thus optimizing the chances of the cell surviving. Data are available from ProteomeXchange with the identifier PXD041121.
AB - Skin pigmentation is paused after sun exposure; however, the mechanism behind this pausing is unknown. In this study, we found that the UVB-induced DNA repair system, led by the ataxia telangiectasia mutated (ATM) protein kinase, represses MITF transcriptional activity of pigmentation genes while placing MITF in DNA repair mode, thus directly inhibiting pigment production. Phosphoproteomics analysis revealed ATM to be the most significantly enriched pathway among all UVB-induced DNA repair systems. ATM inhibition in mouse or human skin, either genetically or chemically, induces pigmentation. Upon UVB exposure, MITF transcriptional activation is blocked owing to ATM-dependent phosphorylation of MITF on S414, which modifies MITF activity and interactome toward DNA repair, including binding to TRIM28 and RBBP4. Accordingly, MITF genome occupancy is enriched in sites of high DNA damage that are likely repaired. This suggests that ATM harnesses the pigmentation key activator for the necessary rapid, efficient DNA repair, thus optimizing the chances of the cell surviving. Data are available from ProteomeXchange with the identifier PXD041121.
KW - DNA Repair Disorders
KW - Pigmentation and Pigment Cell Biology
KW - Transcription Factors
KW - UV radiation
UR - http://www.scopus.com/inward/record.url?scp=85169013905&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2023.03.1686
DO - 10.1016/j.jid.2023.03.1686
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C2 - 37236596
AN - SCOPUS:85169013905
SN - 0022-202X
VL - 143
SP - 2494-2506.e4
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 12
ER -