S-sulfhydration of MEK1 leads to PARP-1 activation and DNA damage repair

EMBO Rep. 2014 Jul;15(7):792-800. doi: 10.1002/embr.201338213. Epub 2014 Apr 28.

Abstract

The repair of DNA damage is fundamental to normal cell development and replication. Hydrogen sulfide (H2S) is a novel gasotransmitter that has been reported to protect cellular aging. Here, we show that H2S attenuates DNA damage in human endothelial cells and fibroblasts by S-sulfhydrating MEK1 at cysteine 341, which leads to PARP-1 activation. H2S-induced MEK1 S-sulfhydration facilitates the translocation of phosphorylated ERK1/2 into nucleus, where it activates PARP-1 through direct interaction. Mutation of MEK1 cysteine 341 inhibits ERK phosphorylation and PARP-1 activation. In the presence of H2S, activated PARP-1 recruits XRCC1 and DNA ligase III to DNA breaks to mediate DNA damage repair, and cells are protected from senescence.

Keywords: H2S; MEK1; PARP‐1; S‐sulfhydration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Damage* / drug effects
  • DNA Repair* / drug effects
  • Enzyme Activation / drug effects
  • Humans
  • Hydrogen Sulfide / pharmacology
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism*
  • MAP Kinase Signaling System
  • Models, Biological
  • Phosphorylation
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protein Processing, Post-Translational

Substances

  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • MAP Kinase Kinase 1
  • Hydrogen Sulfide