Cao Wen-Hui, Wang Xiaogan, Frappart Lucien, Rigal Dominique, Wang Zhao-Qi, Shen Yan, Tong Wei-Min
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5, Dong Dan San Tiao, Beijing 100005, China.
Mutat Res. 2007 Aug 15;632(1-2):20-8. doi: 10.1016/j.mrgentox.2007.04.011. Epub 2007 Apr 21.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that catalyzes the poly(ADP-ribosyl)ation of target proteins in response to DNA damage and has been proposed to play a role in DNA repair, recombination, transcription, cell death, cell proliferation, as well as in stabilization of the genome. We have recently shown that PARP-1 deficiency causes mammary tumorigenesis in mice. In the present study, we investigated whether genetic variants and single nucleotide polymorphisms (SNPs) of PARP-1 contribute to human breast cancer. To this end, we screened all PARP-1 exons, 7.1kb of intron-exon junction and 1.0-kb promoter sequences in 83 French patients with breast cancer and 100 controls by direct sequencing of genomic DNA. Twenty rare genetic variants of PARP-1, including c.1148C>A (Ser383Tyr), c.1354C>A (Arg452Arg), c.2819A>G (Lys940Arg) were detected in nine (10.8%) breast cancers of these patients. Among 31 polymorphic sites examined, five haplotype-tagging SNPs (htSNPs) of PARP-1 were identified. Interestingly, the genotype distribution of htSNP c.852T>C (Ala284Ala) was likely associated with loss of estrogen- and progesterone-receptor expression. The present study implies that genetic variants of PARP-1 may contribute to breast cancerogenesis and that PARP-1 htSNP c.852T>C (Ala284Ala) may influence hormonal therapy of breast cancer.
聚（ADP - 核糖）聚合酶 -1（PARP -1）是一种核酶，可响应DNA损伤催化靶蛋白的聚（ADP - 核糖基）化反应，并且有人提出它在DNA修复、重组、转录、细胞死亡、细胞增殖以及基因组稳定中发挥作用。我们最近发现PARP -1缺陷会导致小鼠发生乳腺肿瘤。在本研究中，我们调查了PARP -1的基因变异和单核苷酸多态性（SNP）是否与人类乳腺癌有关。为此，我们通过对基因组DNA进行直接测序，筛查了83名法国乳腺癌患者和100名对照者的所有PARP -1外显子、7.1kb的内含子 - 外显子连接区和1.0kb的启动子序列。在这些患者的9例（10.8%）乳腺癌中检测到20种PARP -1的罕见基因变异，包括c.1148C>A（Ser383Tyr）、c.1354C>A（Arg452Arg）、c.2819A>G（Lys940Arg）。在检测的31个多态性位点中，鉴定出了PARP -1的5个单倍型标签SNP（htSNP）。有趣的是，htSNP c.852T>C（Ala284Ala）的基因型分布可能与雌激素和孕激素受体表达缺失有关。本研究表明，PARP -1的基因变异可能与乳腺癌发生有关，并且PARP -1 htSNP c.852T>C（Ala284Ala）可能影响乳腺癌的激素治疗。
