Accumulation of Pax2 Transactivation Domain Interaction Protein (PTIP) at Sites of DNA Breaks via RNF8-dependent Pathway Is Required for Cell Survival after DNA Damage
Accumulation of Pax2 Transactivation Domain Interaction Protein (PTIP) at Sites of DNA Breaks via RNF8-dependent Pathway Is Required for Cell Survival after DNA Damage
复制标题
DOI：
10.1074/jbc.m809158200
复制
发表时间：
2009-03-13
影响因子：
4.8
通讯作者：
Chen, Junjie
中科院分区：
文献类型：
--
作者：
Gong, Zihua;Cho, Young-Wook;Chen, Junjie
真核细胞中基因组的稳定性是通过多种细胞事件的协调来维持的，包括细胞周期检查点、DNA修复、转录和DNA损伤后的凋亡。Pax 2反式激活结构域相互作用蛋白（PTIP）是一种含有6个BRCT结构域的蛋白质，参与DNA损伤反应。在这项研究中，我们发现PTIP向受损染色质的募集依赖于DNA损伤信号蛋白γ H2 AX中心点MDC 1中心点RNF 8，这反过来又促进了PA 1（PTIP相关蛋白1）持续定位于DNA断裂位点。与PTIP类似，PA 1的缺失增加了细胞对电离辐射的敏感性。此外，我们证明了PTIP的N-末端PA 1结合结构域和C-末端焦点定位结构域对于PTIP在DNA损伤修复中的功能是至关重要的。有趣的是，虽然PTIP和PA 1与MLL（混合谱系白血病）复合物结合并参与转录调控，但PTIP中心点PA 1在DNA损伤反应中的这种功能可能不依赖于MLL复合物。综上所述，我们认为PTIP中心点PA 1复合物的一个子集通过RNF 8依赖性途径被招募到DNA损伤位点，并且是细胞存活所需的。
Genomic stability in eukaryotic cells is maintained by the coordination of multiple cellular events including cell cycle checkpoint, DNA repair, transcription, and apoptosis after DNA damage. Pax2 transactivation domain interaction protein (PTIP), a protein that contains six BRCT domains, has been implicated in DNA damage response. In this study we showed that recruitment of PTIP to damaged chromatin depends on DNA damage signaling proteins gamma H2AX center dot MDC1 center dot RNF8, which in turn facilitates sustained localization of PA1 (PTIP-associated protein 1) to sites of DNA break. Similar to PTIP, depletion of PA1 increases cellular sensitivity to ionizing radiation. Furthermore, we demonstrated that the N-terminal PA1 binding domain and the C-terminal focus-localization domain of PTIP are critical for PTIP function in DNA damage repair. Interestingly, although PTIP and PA1 associate with MLL (mixed lineage leukemia) complexes and participate in transcriptional regulation, this function of PTIP center dot PA1 in DNA damage response is likely to be independent of the MLL complexes. Taken together, we propose that a subset of PTIP center dot PA1 complex is recruited to DNA damage sites via the RNF8-dependent pathway and is required for cell survival in response to DNA damage.