Xu Qianhua, Wang Fengchao, Xiang Yunlong, Zhang Xiaoxin, Zhao Zhen-Ao, Gao Zheng, Liu Wenbo, Lu Xukun, Liu Yusheng, Yu Xing-Jiang, Wang Haibin, Huang Jun, Yi Zhaohong, Gao Shaorong, Li Lei
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China.
National Institute of Biological Sciences, Beijing 102206, China.
Development. 2015 Nov 15;142(22):3943-53. doi: 10.1242/dev.129841. Epub 2015 Oct 1.
Mammalian early embryos maintain accurate genome integrity for proper development within a programmed timeline despite constant assaults on their DNA by replication, DNA demethylation and genetic defects transmitted from germ cells. However, how genome integrity is safeguarded during mammalian early embryonic development remains unclear. BCAS2 (breast carcinoma amplified sequence 2), a core component of the PRP19 complex involved in pre-mRNA splicing, plays an important role in the DNA damage response through the RPA complex, a key regulator in the maintenance of genome integrity. Currently, the physiological role of BCAS2 in mammals is unknown. We now report that BCAS2 responds to endogenous and exogenous DNA damage in mouse zygotes. Maternal depletion of BCAS2 compromises the DNA damage response in early embryos, leading to developmental arrest at the two- to four-cell stage accompanied by the accumulation of damaged DNA and micronuclei. Furthermore, BCAS2 mutants that are unable to bind RPA1 fail in DNA repair during the zygotic stage. In addition, phosphorylated RPA2 cannot localise to the DNA damage sites in mouse zygotes with disrupted maternal BCAS2. These data suggest that BCAS2 might function through the RPA complex during DNA repair in zygotes. Together, our results reveal that maternal BCAS2 maintains the genome integrity of early embryos and is essential for female mouse fertility.
哺乳动物早期胚胎在程序化的时间轴内保持准确的基因组完整性，以实现正常发育，尽管其DNA不断受到复制、DNA去甲基化以及生殖细胞传递的遗传缺陷的攻击。然而，在哺乳动物早期胚胎发育过程中基因组完整性是如何得到保障的仍不清楚。BCAS2（乳腺癌扩增序列2）是参与前体mRNA剪接的PRP19复合体的核心成分，通过RPA复合体在DNA损伤反应中发挥重要作用，RPA复合体是维持基因组完整性的关键调节因子。目前，BCAS2在哺乳动物中的生理作用尚不清楚。我们现在报告，BCAS2在小鼠受精卵中对内源性和外源性DNA损伤作出反应。母源BCAS2的缺失会损害早期胚胎中的DNA损伤反应，导致在二细胞到四细胞阶段发育停滞，并伴有受损DNA和微核的积累。此外，无法结合RPA1的BCAS2突变体在合子期的DNA修复中失败。另外，在母源BCAS2缺失的小鼠受精卵中，磷酸化的RPA2无法定位到DNA损伤位点。这些数据表明，BCAS2可能在受精卵的DNA修复过程中通过RPA复合体发挥作用。总之，我们的结果表明母源BCAS2维持早期胚胎的基因组完整性，对雌性小鼠的生育能力至关重要。
