Abstract：
DNA damage leads to rapid synthesis of poly(ADP-ribose) (pADPr), which is important for damage signaling and repair. pADPr chains are removed by poly(ADP-ribose) glycohydrolase (PARG), releasing free mono(ADP-ribose) (mADPr). Here, we show that the NUDIX hydrolase NUDT5, which can hydrolyze mADPr to ribose-5-phosphate and either AMP or ATP, is recruited to damage sites through interaction with PARG. NUDT5 does not regulate PARP or PARG activity. Instead, loss of NUDT5 reduces basal cellular ATP levels and exacerbates the decrease in cellular ATP that occurs during DNA repair. Further, loss of NUDT5 activity impairs RAD51 recruitment, attenuates the phosphorylation of key DNA-repair proteins, and reduces both H2A.Z exchange at damage sites and repair by homologous recombination. The ability of NUDT5 to hydrolyze mADPr, and/or regulate cellular ATP, may therefore be important for efficient DNA repair. Targeting NUDT5 to disrupt PAR/mADPr and energy metabolism may be an effective anti-cancer strategy.
摘要：
DNA损伤导致聚（ADP-核糖）（pADPr）的快速合成，这对于损坏信号和修复很重要。pADPr链通过聚（ADP-核糖）糖水解酶（PARG）去除，释放游离单（ADP-核糖）（mADPr）。这里,我们表明NUDIX水解酶NUDT5，它可以将mADPr水解为核糖-5-磷酸和AMP或ATP，通过与PARG的互动被招募来破坏站点。NUDT5不调节PARP或PARG活性。相反，NUDT5的缺失降低了基础细胞ATP水平并加剧了DNA修复过程中发生的细胞ATP的减少。Further,NUDT5活动的丧失削弱了RAD51的招募，减弱关键DNA修复蛋白的磷酸化，并降低了H2A。在损伤位点进行Z交换并通过同源重组进行修复。NUDT5水解mADPr的能力，和/或调节细胞ATP，因此对于有效的DNA修复可能是重要的。靶向NUDT5破坏PAR/mADPr和能量代谢可能是一种有效的抗癌策略。
