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Title: PARP1 Val762Ala polymorphism reduces enzymatic activity

Abstract

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 {sub m} of PARP1-Ala762 was increased to a 1.2-fold of the K {sub m} of PARP1-Val762 for trans-poly(ADP-ribosyl)ation. Thus, the PARP1 Val762Ala polymorphism reduces the enzymatic activity of PARP1 by increasing K {sub m}. This finding suggests that different levels of poly(ADP-ribosyl)ation by PARP1 might aid in understanding Cancer risk of carriers of the PARP1 Val762Ala polymorphism.

Authors:
 [1];  [2];  [3];  [4];  [1]
  1. 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 (China)
  2. (IARC), 150 cours Albert-Thomas, 69008 Lyon (France)
  3. International Agency for Research on Cancer (IARC), 150 cours Albert-Thomas, 69008 Lyon (France)
  4. International Agency for Research on Cancer (IARC), 150 cours Albert-Thomas, 69008 Lyon (France). E-mail: tong@iarc.fr
Publication Date:
OSTI Identifier:
20979814
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 354; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2006.12.162; PII: S0006-291X(06)02836-1; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADP; ALANINES; IN VITRO; NEOPLASMS; POLYMERASES; RIBOSE; VALINE

Citation Formats

Wang Xiaogan, International Agency for Research on Cancer, Wang Zhaoqi, Tong Weimin, and Shen Yan. PARP1 Val762Ala polymorphism reduces enzymatic activity. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2006.12.162.
Wang Xiaogan, International Agency for Research on Cancer, Wang Zhaoqi, Tong Weimin, & Shen Yan. PARP1 Val762Ala polymorphism reduces enzymatic activity. United States. doi:10.1016/j.bbrc.2006.12.162.
Wang Xiaogan, International Agency for Research on Cancer, Wang Zhaoqi, Tong Weimin, and Shen Yan. Fri . "PARP1 Val762Ala polymorphism reduces enzymatic activity". United States. doi:10.1016/j.bbrc.2006.12.162.
@article{osti_20979814,
title = {PARP1 Val762Ala polymorphism reduces enzymatic activity},
author = {Wang Xiaogan and International Agency for Research on Cancer and Wang Zhaoqi and Tong Weimin and Shen Yan},
abstractNote = {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 {sub m} of PARP1-Ala762 was increased to a 1.2-fold of the K {sub m} of PARP1-Val762 for trans-poly(ADP-ribosyl)ation. Thus, the PARP1 Val762Ala polymorphism reduces the enzymatic activity of PARP1 by increasing K {sub m}. This finding suggests that different levels of poly(ADP-ribosyl)ation by PARP1 might aid in understanding Cancer risk of carriers of the PARP1 Val762Ala polymorphism.},
doi = {10.1016/j.bbrc.2006.12.162},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 354,
place = {United States},
year = {Fri Mar 02 00:00:00 EST 2007},
month = {Fri Mar 02 00:00:00 EST 2007}
}