Maternal BCAS2 protects genomic integrity in mouse early embryonic development

Abstract

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.

Double maternal effect: duplicated nucleoplasmin 2 genes,npm2aandnpm2b, are shared by fish and tetrapods, and have distinct and essential roles in early embryogenesis

“…In contrast, npm2b appears to function at a later stage or other factors can replace its role in the early stages as the npm2b -deficient embryos are capable of dividing until around 4 hpf, which corresponds to previous reports [8,14]. These findings are in line with those demonstrated for other maternal-effect genes in mammals, such as mater , floped , filia , tle6 [47], and bcas2 [48] as well as in zebrafish, including fue [49] and cellular atoll [50], all of which function to moderate the early events of fertilization and embryogenesis and their ablation leads to arrest and mortality at the earliest stages of embryogenesis.…”

Maternal DCAF2 is crucial for maintenance of genome stability during the first cell cycle in mice

“…(3) the DNA replication in the zygote is accompanied by drastic genome remodeling, including massive DNA demethylation, histone modifications and histone replacement (Akiyama et al, 2011;Murai et al, 2014;Swiech et al, 2007;Xu et al, 2015). It has been proposed that genome remodeling after fertilization, particularly in the male nucleus, induces DNA damage including both single-and doublestrand breaks (Hajkova et al, 2010;Nakatani et al, 2015).…”

Conditional Knockout of Breast Carcinoma Amplified Sequence 2 (BCAS2) in Mouse Forebrain Causes Dendritic Malformation via β-catenin

“…Knockdown of the BCAS2/spf27 subunit destabilizes the hPrp19 complex, which results in mitotic defects 9 . BCAS2 was recently found to be an essential gene during the embryonic stage 10 . We previously reported that wing-specific knockdown of BCAS2 causes Drosophila wing developmental defects 11 ; due to BCAS2 participates in Delta pre-mRNA splicing and regulates the Delta-Notch signaling 12 .…”