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KHDC3L Mutation Causes Recurrent Pregnancy Loss by Inducing Genomic Instability of Human Early Embryonic Cells
论文题目: KHDC3L Mutation Causes Recurrent Pregnancy Loss by Inducing Genomic Instability of Human Early Embryonic Cells
作者: Zhang W, Chen Z, Zhang D, Zhao B, Liu L, Xie Z, Yao Y, Zheng P
联系作者: zhengp@mail.kiz.ac.cn
发表年度: 2019
DOI: doi: 10.1371/journal.pbio.3000468
摘要: Recurrent pregnancy loss (RPL) is an important complication in reproductive health. About 50% of RPL cases are unexplained, and understanding the genetic basis is essential for its diagnosis and prognosis. Herein, we report causal KH domain containing 3 like (KHDC3L) mutations in RPL. KHDC3L is expressed in human epiblast cells and ensures their genome stability and viability. Mechanistically, KHDC3Lbinds to poly(ADP-ribose) polymerase 1 (PARP1) to stimulate its activity. In response to DNA damage, KHDC3L also localizes to DNA damage sites and facilitates homologous recombination (HR)-mediated DNA repair. KHDC3L dysfunction causes PARP1 inhibition and HR repair deficiency, which is synthetically lethal. Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions. Importantly, two deletions of KHDC3L (p.E150_V160del and p.E150_V172del) were detected in female RPL patients, both of which harbor a common loss of Thr156 and are impaired in PARP1 activation and HR repair. In summary, our study reveals both KHDC3L as a new RPL risk gene and its critical function in DNA damage repair pathways
刊物名称: PLos Biology
论文出处: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000468
影响因子: 8.386(2018年)
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