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

Nadav Elkoshi1, Shivang Parikh1, Hagar Malcov-Brog1

  • 1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The Journal of Investigative Dermatology
|May 26, 2023
PubMed

Insights

Sun exposure pauses skin pigmentation by activating the ataxia telangiectasia mutated (ATM) DNA repair system. This system inhibits MITF, a key pigmentation activator, redirecting it to DNA repair, thus preventing pigment production.

Area of Science:

  • Molecular biology
  • Dermatology
  • Genetics

Background:

  • Skin pigmentation is regulated by microphthalmia-associated transcription factor (MITF).
  • The mechanism by which sun exposure temporarily halts pigmentation remains unclear.
  • DNA damage response pathways are crucial for cellular survival after UV radiation.

Purpose of the Study:

  • To elucidate the molecular mechanism underlying the suppression of skin pigmentation following sun exposure.
  • To investigate the role of DNA repair pathways in regulating pigmentation.
  • To identify key proteins involved in the UV-induced inhibition of pigment production.

Main Methods:

  • UVB irradiation of mouse and human skin models.
  • Phosphoproteomics analysis to identify key signaling pathways.
  • Genetic and chemical inhibition of ataxia telangiectasia mutated (ATM) protein kinase.
  • MITF activity assays and MITF-DNA binding analysis.
  • Analysis of MITF phosphorylation and interactome.

Main Results:

  • UVB exposure activates the ATM protein kinase, a central component of the DNA damage response.
  • ATM-dependent phosphorylation of MITF at S414 redirects MITF from pigmentation genes to DNA repair sites.
  • ATM inhibition leads to increased skin pigmentation in mouse and human skin.
  • MITF's interaction with TRIM28 and RBBP4 is enhanced upon UVB exposure, facilitating DNA repair.

Conclusions:

  • The ATM DNA repair pathway directly inhibits skin pigmentation by modifying MITF activity and localization.
  • ATM harnesses MITF, a key pigmentation regulator, for efficient DNA repair after UV damage.
  • This mechanism ensures cellular survival by prioritizing DNA repair over pigment production post-sun exposure.
Keywords:
DNA Repair DisordersPigmentation and Pigment Cell BiologyTranscription FactorsUV radiation

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