Maternal BCAS2 protects genomic integrity in mouse early embryonic development
Maternal BCAS2 protects genomic integrity in mouse early embryonic development
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DOI：
10.1242/dev.129841
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发表时间：
2015-11
期刊：
影响因子：
4.6
通讯作者：
Qianhua Xu;Fengchao Wang;Yunlong Xiang;Xiaoxin Zhang;Zhen-Ao Zhao;Zheng Gao;Wenbo Liu;Xukun Lu;Yusheng Liu;Xingjiang Yu;Haibin Wang;Jun Huang;Zhaohong Yi;Shaorong Gao;Lei Li
中科院分区：
文献类型：
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作者：
Qianhua Xu;Fengchao Wang;Yunlong Xiang;Xiaoxin Zhang;Zhen-Ao Zhao;Zheng Gao;Wenbo Liu;Xukun Lu;Yusheng Liu;Xingjiang Yu;Haibin Wang;Jun Huang;Zhaohong Yi;Shaorong Gao;Lei Li
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进行适当的发育，尽管它们的DNA受到复制、DNA去甲基化和从生殖细胞传递的遗传缺陷的不断攻击。然而，在哺乳动物早期胚胎发育过程中，基因组的完整性是如何得到保护的仍不清楚。BCAS 2（乳腺癌扩增序列2）是参与前体mRNA剪接的PRP 19复合物的核心组分，通过RPA复合物在DNA损伤反应中起重要作用，RPA复合物是维持基因组完整性的关键调节因子。目前，BCAS 2在哺乳动物中的生理作用尚不清楚。我们现在报告BCAS 2对小鼠受精卵中内源性和外源性DNA损伤的反应。BCAS 2的母体消耗会损害早期胚胎的DNA损伤反应，导致发育停滞在2 - 4细胞阶段，伴随着受损DNA和微核的积累。此外，不能结合RPA 1的BCAS 2突变体在合子阶段的DNA修复中失败。此外，磷酸化的RPA 2不能定位于具有破坏的母体BCAS 2的小鼠受精卵中的DNA损伤位点。这些数据表明，BCAS 2可能通过RPA复合物在受精卵的DNA修复过程中发挥作用。总之，我们的研究结果表明，母体BCAS 2保持了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。总结：在早期小鼠胚胎中，DNA损伤修复是通过BCAS 2介导的RPA复合物的控制来实现的，RPA复合物是基因组完整性的关键调节因子。
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. Summary: In the early mouse embryo, DNA damage repair is achieved through BCAS2-mediated control of the RPA complex, a key regulator of genome integrity.