KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells.
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 expr...
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2019-10-01
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doaj-8568c646525c4cbfaaf43c07cd7cf22c2021-07-02T21:22:15ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852019-10-011710e300046810.1371/journal.pbio.3000468KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells.Weidao ZhangZhongliang ChenDengfeng ZhangBo ZhaoLu LiuZhengyuan XieYonggang YaoPing ZhengRecurrent 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.https://doi.org/10.1371/journal.pbio.3000468 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Weidao Zhang Zhongliang Chen Dengfeng Zhang Bo Zhao Lu Liu Zhengyuan Xie Yonggang Yao Ping Zheng |
spellingShingle |
Weidao Zhang Zhongliang Chen Dengfeng Zhang Bo Zhao Lu Liu Zhengyuan Xie Yonggang Yao Ping Zheng KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells. PLoS Biology |
author_facet |
Weidao Zhang Zhongliang Chen Dengfeng Zhang Bo Zhao Lu Liu Zhengyuan Xie Yonggang Yao Ping Zheng |
author_sort |
Weidao Zhang |
title |
KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells. |
title_short |
KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells. |
title_full |
KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells. |
title_fullStr |
KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells. |
title_full_unstemmed |
KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells. |
title_sort |
khdc3l mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2019-10-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pbio.3000468 |
work_keys_str_mv |
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