Melanocyte-stimulating hormone directly enhances UV-Induced DNA repair in keratinocytes by a xeroderma pigmentosum group A-dependent mechanism

Cancer Res. 2010 May 1;70(9):3547-56. doi: 10.1158/0008-5472.CAN-09-4596. Epub 2010 Apr 13.

Abstract

Melanocyte-stimulating hormone (MSH) reduces UV-induced DNA damage through the induction of pigmentation. In this study, we provide evidence that MSH also enhances DNA repair in skin keratinocytes by modulating the function of DNA repair molecules. Intracutaneous injection of MSH prevented UV-induced DNA damage in human and mouse skin independent of its effects on melanogenesis. In keratinocytes, MSH bound to the melanocyte melanocortin receptor type 1 and activated adenylate cyclase activity, which in turn activated Xeroderma pigmentosum group A (XPA)-binding protein 1 and induced nuclear translocation of XPA, a critical factor controlling nucleotide excision repair signaling pathways. Together, our findings reveal a novel pigmentation-independent mechanism that underlies MSH-mediated DNA repair following UVB irradiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cyclic AMP / metabolism
  • DNA Damage
  • DNA Repair / drug effects*
  • DNA Repair / radiation effects*
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / physiology*
  • Keratinocytes / radiation effects
  • Receptor, Melanocortin, Type 1 / metabolism
  • Signal Transduction
  • Ultraviolet Rays
  • Xeroderma Pigmentosum Group A Protein / metabolism*
  • alpha-MSH / pharmacology*

Substances

  • Guanine Nucleotide Exchange Factors
  • RAPGEF3 protein, human
  • Receptor, Melanocortin, Type 1
  • XPA protein, human
  • Xeroderma Pigmentosum Group A Protein
  • alpha-MSH
  • Cyclic AMP
  • GPN1 protein, human
  • GTP-Binding Proteins