KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells
KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells
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KHDC3L突变通过诱导人类早期胚胎细胞基因组不稳定导致反复流产
DOI：
10.1371/journal.pbio.3000468
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发表时间：
2019-10-01
期刊：
影响因子：
9.8
通讯作者：
Zheng，Ping
中科院分区：
文献类型：
--
作者：
Zhang，Weidao;Chen，Zhongliang;Zheng，Ping
复发性妊娠丢失是影响生殖健康的重要并发症。约50%的RPL病例无法解释，了解遗传基础对其诊断和预后至关重要。在此，我们报告了RPL中含有3样（KHDC3L）突变的因果KH结构域。KHDC3L在人外胚层细胞中表达，确保其基因组的稳定性和活力。机制上，KHDC3L结合聚（adp -核糖）聚合酶1 （PARP1）以刺激其活性。在DNA损伤反应中，KHDC3L也定位于DNA损伤位点，促进同源重组（homologous recombination， HR）介导的DNA修复。KHDC3L功能障碍导致PARP1抑制和HR修复缺陷，具有综合致死性。值得注意的是，我们发现了两个关键残基Thr145和Thr156，它们被ataxa -毛细血管扩张突变（ATM）磷酸化对KHDC3L的功能至关重要。重要的是，在女性RPL患者中检测到两个KHDC3L缺失（p.E150_V160del和p.E150_V172del），这两个缺失都含有常见的Thr156缺失，并且在PARP1激活和HR修复中受损。总之，我们的研究揭示了KHDC3L作为一种新的RPL风险基因及其在DNA损伤修复途径中的关键功能。
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, KHDC3L binds 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.