Mochizuki Ayako L, Katanaya Ami, Hayashi Eri, Hosokawa Mihoko, Moribe Emiko, Motegi Akira, Ishiai Masamichi, Takata Minoru, Kondoh Gen, Watanabe Hitomi, Nakatsuji Norio, Chuma Shinichiro
Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Mol Cell Biol. 2017 Nov 13;37(23). doi: 10.1128/MCB.00117-17. Print 2017 Dec 1.
DNA replication is frequently perturbed by intrinsic, as well as extrinsic, genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain genome integrity. We show here that PARI antirecombinase plays an essential role in modulating the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent-strand shortening that is regulated by RAD51 and MRE11. PARI then promotes double-strand break induction, followed by new origin firing instead of replication restart. Such PARI function is apparently obstructive to replication but is nonetheless physiologically required for chromosome stability and Of note, -deficient embryonic stem cells exhibit spontaneous chromosome instability, which is attenuated by differentiation induction, suggesting that pluripotent stem cells have a preferential requirement for PARI that acts against endogenous replication stress. PARI is a latent modulator of stalled fork processing, which is required for stable genome inheritance under both endogenous and exogenous replication stress in mice.
DNA复制经常受到内在和外在基因毒性应激的干扰。在受损的复制叉处，DNA复制和修复活动需要适当协调以维持基因组完整性。我们在此表明，PARI抗重组酶在调节小鼠对复制应激的初始反应中起重要作用。在正常复制过程中，PARI在复制体上功能休眠，但在复制应激时，它会增强由RAD51和MRE11调节的新生链缩短。然后，PARI促进双链断裂诱导，随后引发新的起始点而不是复制重新启动。这种PARI功能显然对复制有阻碍作用，但对于染色体稳定性在生理上却是必需的。值得注意的是，PARI缺陷的胚胎干细胞表现出自发性染色体不稳定，这种不稳定通过诱导分化而减弱，这表明多能干细胞对抵抗内源性复制应激的PARI有优先需求。PARI是停滞复制叉处理的潜在调节因子，这是小鼠在内源性和外源性复制应激下稳定基因组遗传所必需的。
