PTIP promotes DNA double-strand break repair through homologous recombination
PTIP promotes DNA double-strand break repair through homologous recombination
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DOI：
10.1111/j.1365-2443.2009.01379.x
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发表时间：
2010-03-01
期刊：
影响因子：
2.1
通讯作者：
Takeda, Shunichi
中科院分区：
文献类型：
--
作者：
Wang, Xin;Takenaka, Katsuya;Takeda, Shunichi
PTIP （Pax2 transactivation domain-interacting protein）是一种含有6个BRCT （BRCA1 C-Terminal）结构域的大核蛋白。PTIP通过其BRCT结构域被招募到DNA损伤位点，因此与DNA损伤反应有关。为了明确PTIP在DNA修复中的功能，我们破坏了鸡DT40 B细胞系的PTIP基因。PTIP突变（PTIP-/-/-）细胞表现出在同源重组缺陷（HR）细胞中经常观察到的表型，即自发产生的DNA损伤数量显著增加，对电离辐射（IR）和拓扑异构酶I抑制剂喜树碱敏感。因此，人工重组底物对HR效率的分析表明，在ptip缺失的鸡和ptip缺失的HeLa细胞中，HR效率降低。由于微阵列分析显示野生型和PTIP-/-/-细胞在已知HR因子的表达上没有明显差异，因此PTIP缺陷细胞中HR效率的降低不太可能与PTIP在转录调节中的作用有关。因此，我们提出PTIP通过直接作用于HR促进双链断裂修复。
PTIP (Pax2 transactivation domain-interacting protein) is a large nuclear protein containing six BRCT (BRCA1 C-Terminal) domains. PTIP is recruited to DNA-damage sites through its BRCT domains and thus has been implicated in the DNA damage response. To define the function of PTIP in DNA repair, we disrupted the PTIP gene of the chicken DT40 B cell line. PTIP mutant (PTIP-/-/-) cells displayed phenotypes frequently observed in cells with defective homologous recombination (HR), i.e. a marked increase in the number of spontaneously arising DNA lesions as well as sensitivity to ionizing radiation (IR) and the topoisomerase I inhibitor, camptothecin. Accordingly, analysis of HR efficiency by using artificial recombination substrates showed that the HR efficiency was reduced in the PTIP-deficient chicken and the PTIP-depleted HeLa cells. As microarray analysis showed no apparent difference between wild-type and PTIP-/-/- cells in the expression of known HR factors, it is unlikely that this reduction in HR efficiency in PTIP-deficient cells is associated with PTIP's role in transcriptional regulation. We thus propose that PTIP promotes double-strand break repair through a direct role in HR.