PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage

Mol Cell. 2014 Jun 19;54(6):999-1011. doi: 10.1016/j.molcel.2014.05.030.

Abstract

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

Publication types

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

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / chemistry
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • DNA Damage*
  • DNA Repair / genetics
  • DNA-Binding Proteins / genetics
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred C57BL
  • Mutagenesis / radiation effects
  • Phosphorylation / radiation effects
  • Pigmentation / genetics
  • Protein Processing, Post-Translational / genetics
  • Protein Processing, Post-Translational / radiation effects
  • RNA Interference
  • RNA, Small Interfering
  • Receptor, Melanocortin, Type 1 / genetics*
  • Signal Transduction / genetics
  • Signal Transduction / radiation effects
  • Ultraviolet Rays
  • Xeroderma Pigmentosum Group A Protein / genetics
  • Xeroderma Pigmentosum Group A Protein / metabolism*

Substances

  • DNA-Binding Proteins
  • RNA, Small Interfering
  • Receptor, Melanocortin, Type 1
  • XPA protein, human
  • Xeroderma Pigmentosum Group A Protein
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Cyclic AMP-Dependent Protein Kinases