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.

• Authors: Qianhua Xu, Fengchao Wang, Yunlong Xiang, Xiaoxin Zhang, Zhen-Ao Zhao, Zheng Gao, Wenbo Liu, Xukun Lu, Yusheng Liu, Xing-Jiang Yu, Haibin Wang, Jun Huang, Zhaohong Yi, Shaorong Gao, Lei Li
• Journal: Development (Cambridge, England) (Development) Vol. 142 Issue 22 Pg. 3943-53 (Nov 15 2015) ISSN: 1477-9129 [Electronic] England
• PMID: 26428007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015. Published by The Company of Biologists Ltd.

Chemical References

• BCAS2 protein, mouse
• Multiprotein Complexes
• Neoplasm Proteins
• Nuclear Matrix-Associated Proteins
• Prpf19 protein, mouse
• RNA Splicing Factors
• Replication Protein A
• Rpa1 protein, mouse

Topics

• Animals
• Blotting, Western
• DNA Repair (genetics, physiology)
• Embryonic Development (genetics, physiology)
• Female
• Fertility (genetics, physiology)
• Gene Targeting
• Genomic Instability (genetics, physiology)
• In Situ Nick-End Labeling
• Mice
• Microscopy, Fluorescence
• Multiprotein Complexes (metabolism)
• Neoplasm Proteins (metabolism)
• Nuclear Matrix-Associated Proteins (metabolism)
• Pregnancy
• RNA Splicing Factors
• Real-Time Polymerase Chain Reaction
• Replication Protein A (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction