PMID:21966279

Citation	Lu, H, Huang, YY, Mehrotra, S, Droz-Rosario, R, Liu, J, Bhaumik, M, White, E and Shen, Z (2011) Essential roles of BCCIP in mouse embryonic development and structural stability of chromosomes. PLoS Genet. 7:e1002291
Abstract	BCCIP is a BRCA2- and CDKN1A(p21)-interacting protein that has been implicated in the maintenance of genomic integrity. To understand the in vivo functions of BCCIP, we generated a conditional BCCIP knockdown transgenic mouse model using Cre-LoxP mediated RNA interference. The BCCIP knockdown embryos displayed impaired cellular proliferation and apoptosis at day E7.5. Consistent with these results, the in vitro proliferation of blastocysts and mouse embryonic fibroblasts (MEFs) of BCCIP knockdown mice were impaired considerably. The BCCIP deficient mouse embryos die before E11.5 day. Deletion of the p53 gene could not rescue the embryonic lethality due to BCCIP deficiency, but partially rescues the growth delay of mouse embryonic fibroblasts in vitro. To further understand the cause of development and proliferation defects in BCCIP-deficient mice, MEFs were subjected to chromosome stability analysis. The BCCIP-deficient MEFs displayed significant spontaneous chromosome structural alterations associated with replication stress, including a 3.5-fold induction of chromatid breaks. Remarkably, the BCCIP-deficient MEFs had a ∼20-fold increase in sister chromatid union (SCU), yet the induction of sister chromatid exchanges (SCE) was modestly at 1.5 fold. SCU is a unique type of chromatid aberration that may give rise to chromatin bridges between daughter nuclei in anaphase. In addition, the BCCIP-deficient MEFs have reduced repair of irradiation-induced DNA damage and reductions of Rad51 protein and nuclear foci. Our data suggest a unique function of BCCIP, not only in repair of DNA damage, but also in resolving stalled replication forks and prevention of replication stress. In addition, BCCIP deficiency causes excessive spontaneous chromatin bridges via the formation of SCU, which can subsequently impair chromosome segregations in mitosis and cell division.
Links	PubMed PMC3178617 Online version:10.1371/journal.pgen.1002291
Keywords	Animals; BRCA2 Protein/genetics; BRCA2 Protein/metabolism; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Chromosomal Instability/genetics; Chromosome Segregation; Cyclin-Dependent Kinase Inhibitor p21/genetics; Cyclin-Dependent Kinase Inhibitor p21/metabolism; DNA Damage/genetics; DNA Repair/genetics; DNA Replication/genetics; Embryonic Development/genetics; Fibroblasts/cytology; Fibroblasts/metabolism; Mice; Mice, Transgenic; Rad51 Recombinase/genetics; Rad51 Recombinase/metabolism; Recombination, Genetic; Sister Chromatid Exchange
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:BCCIP		GO:0006974: cellular response to DNA damage stimulus	ECO:0000315:		P		Figure 7. BCCIP Knockdown cells exhibit greater growth inhibition by irradiation compared to control.	complete CACAO 3994
MOUSE:BCCIP	involved_in	GO:0006974: cellular response to DNA damage stimulus	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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