S-sulfhydration of MEK1 leads to PARP-1 activation and DNA damage repair.
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.
Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, ON, Canada The School of Kinesiology Lakehead University, Thunder Bay, ON, Canada.
Kexin
K
Zhao
Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, ON, Canada The School of Kinesiology Lakehead University, Thunder Bay, ON, Canada.
YoungJun
Y
Ju
Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, ON, Canada The School of Kinesiology Lakehead University, Thunder Bay, ON, Canada.
Shuangshuang
S
Li
Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, ON, Canada Department of Biology, Lakehead University, Thunder Bay, ON, Canada.
Zaid
Z
Altaany
Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, ON, Canada Department of Biology, Lakehead University, Thunder Bay, ON, Canada.
Rui
R
Wang
Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, ON, Canada The School of Kinesiology Lakehead University, Thunder Bay, ON, Canada gyang@lakeheadu.ca.
Guangdong
G
Yang
D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048369:MAP Kinase Kinase 1; D006862:Hydrogen Sulfide
H2S; MEK1; PARP‐1; S‐sulfhydration