PARP1 Val762Ala polymorphism reduces enzymatic activity.
Poly(ADP-ribose) polymerase 1 (PARP1) modifies a variety of nuclear proteins by poly(ADP-ribosyl)ation, and plays diverse roles in molecular and cellular processes. A common PARP1 single nucleotide polymorphism (SNP) at codon 762, resulting in the substitution of alanine (Ala) for valine (Val) in the catalytic domain has been implicated in susceptibility to cancer. To characterize the functional effect of this polymorphism on PARP1, we performed in vitro enzymatic analysis on PARP1-Ala762 and PARP1-Val762. We found that PARP1-Ala762 displayed 57.2% of the activity of PARP1-Val762 for auto-poly(ADP-ribosyl)ation and 61.9% of the activity of PARP1-Val762 for trans-poly(ADP-ribosyl)ation of histone H1. The kinetic characterization revealed that the K(m) of PARP1-Ala762 was increased to a 1.2-fold of the K(m) of PARP1-Val762 for trans-poly(ADP-ribosyl)ation. Thus, the PARP1 Val762Ala polymorphism reduces the enzymatic activity of PARP1 by increasing K(m). This finding suggests that different levels of poly(ADP-ribosyl)ation by PARP1 might aid in understanding the cancer risk of carriers of the PARP1 Val762Ala polymorphism.
Wang
Xiao-Gan
XG
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), 5 Dong Dan San Tiao, 100005 Beijing, PR China.
Wang
Zhao-Qi
ZQ
Tong
Wei-Min
WM
Shen
Yan
Y
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013329:Structure-Activity Relationship
C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases