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

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

doi:10.1016/j.jid.2023.03.1686

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

Nadav Elkoshi
, Shivang Parikh
, Hagar Malcov-Brog
, Roma Parikh
, Paulee Manich
, Francesca Netti
, Avishai Maliah
, Hana Elkoshi
, Majd Haj
, Ido Rippin
, Jacob Frand
, Tomer Perluk
, Rivi Haiat-Factor
, Tamar Golan
, Neta Regev-Rudzki
, Edo Kiper
, Ronen Brenner
, Pinchas Gonen
, Iris Dror
, Hagai Levi

Ofir Hameiri, Mazal Cohen-Gulkar, Hagit Eldar-Finkelman, Gil Ast, Eran Nizri, Yael Ziv, Rani Elkon, Mehdi Khaled, Yuval Ebenstein, Yosef Shiloh, Carmit Levy

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	2494-2506.e4
Journal	Journal of Investigative Dermatology
Volume	143
Issue number	12
DOIs	https://doi.org/10.1016/j.jid.2023.03.1686
State	Published - 1 Dec 2023
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

DNA Repair Disorders
Pigmentation and Pigment Cell Biology
Transcription Factors
UV radiation

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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10.1016/j.jid.2023.03.1686

Cite this

Elkoshi, N., Parikh, S., Malcov-Brog, H., Parikh, R., Manich, P., Netti, F., Maliah, A., Elkoshi, H., Haj, M., Rippin, I., Frand, J., Perluk, T., Haiat-Factor, R., Golan, T., Regev-Rudzki, N., Kiper, E., Brenner, R., Gonen, P., Dror, I., ... Levy, C. (2023). Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode. Journal of Investigative Dermatology, 143(12), 2494-2506.e4. https://doi.org/10.1016/j.jid.2023.03.1686

@article{782563f4d5364ba29c4b3d609f873eeb,

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

abstract = "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.",

keywords = "DNA Repair Disorders, Pigmentation and Pigment Cell Biology, Transcription Factors, UV radiation",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

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doi = "10.1016/j.jid.2023.03.1686",

language = "English",

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Elkoshi, N, Parikh, S, Malcov-Brog, H, Parikh, R, Manich, P, Netti, F, Maliah, A, Elkoshi, H, Haj, M, Rippin, I, Frand, J, Perluk, T, Haiat-Factor, R, Golan, T, Regev-Rudzki, N, Kiper, E, Brenner, R, Gonen, P, Dror, I, Levi, H, Hameiri, O, Cohen-Gulkar, M, Eldar-Finkelman, H, Ast, G, Nizri, E, Ziv, Y, Elkon, R, Khaled, M, Ebenstein, Y, Shiloh, Y & Levy, C 2023, 'Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode', Journal of Investigative Dermatology, vol. 143, no. 12, pp. 2494-2506.e4. https://doi.org/10.1016/j.jid.2023.03.1686

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

PY - 2023/12/1

Y1 - 2023/12/1

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 - https://www.scopus.com/pages/publications/85169013905

U2 - 10.1016/j.jid.2023.03.1686

DO - 10.1016/j.jid.2023.03.1686

M3 - Article

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 -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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