PDF(Pubmed)
Abstract：
The intracellular ATP-ribosyltransferases PARP1 and PARP2, contribute to DNA base excision repair (BER) and DNA demethylation and have been implicated in epigenetic programming in early mammalian development. Recently, proteomic analyses identified BER proteins to be covalently poly-ADP-ribosylated by PARPs. The role of this posttranslational modification in the BER process is unknown. Here, we show that PARP1 senses AP-sites and SSBs generated during TET-TDG mediated active DNA demethylation and covalently attaches PAR to each BER protein engaged. Covalent PARylation dissociates BER proteins from DNA, which accelerates the completion of the repair process. Consistently, inhibition of PARylation in mESC resulted both in reduced locus-specific TET-TDG-targeted DNA demethylation, and in reduced general repair of random DNA damage. Our findings establish a critical function of covalent protein PARylation in coordinating molecular processes associated with dynamic DNA methylation.
摘要：
细胞内ATP-核糖基转移酶PARP1和PARP2有助于DNA碱基切除修复（BER）和DNA去甲基化，并参与早期哺乳动物发育的表观遗传编程。最近,蛋白质组学分析确定BER蛋白被PARP共价聚ADP核糖基化。这种翻译后修饰在BER过程中的作用是未知的。这里,我们显示PARP1可感知在TET-TDG介导的活性DNA去甲基化过程中产生的AP位点和SSB，并将PAR共价连接到每个参与的BER蛋白上。共价PARylation从DNA中分离出BER蛋白，这加速了修复过程的完成。始终如一，抑制mESC中的PARylation导致减少的基因座特异性TET-TDG靶向DNA去甲基化，减少随机DNA损伤的一般修复。我们的发现建立了共价蛋白PARylation在协调与动态DNA甲基化相关的分子过程中的关键功能。
