Premium
53 BP 1 ablation rescues genomic instability in mice expressing ‘ RING ‐less’ BRCA 1
Author(s) -
Li Minxing,
Cole Francesca,
Patel Dharm S,
Misenko Sarah M,
Her Joonyoung,
Malhowski Amy,
Alhamza Ali,
Zheng Haiyan,
Baer Richard,
Ludwig Thomas,
Jasin Maria,
Nussenzweig André,
Serrano Lourdes,
Bunting Samuel F
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201642497
Subject(s) - genome instability , biology , dna damage , microbiology and biotechnology , mutation , genetics , mutagenesis , mutant , cancer research , gene , dna
Abstract BRCA 1 mutations strongly predispose affected individuals to breast and ovarian cancer, but the mechanism by which BRCA 1 acts as a tumor suppressor is not fully understood. Homozygous deletion of exon 2 of the mouse Brca1 gene normally causes embryonic lethality, but we show that exon 2‐deleted alleles of Brca1 are expressed as a mutant isoform that lacks the N‐terminal RING domain. This “ RING ‐less” BRCA 1 protein is stable and efficiently recruited to the sites of DNA damage. Surprisingly, robust RAD 51 foci form in cells expressing RING ‐less BRCA 1 in response to DNA damage, but the cells nonetheless display the substantial genomic instability. Genomic instability can be rescued by the deletion of Trp53bp1 , which encodes the DNA damage response factor 53 BP 1, and mice expressing RING ‐less BRCA 1 do not show an increased susceptibility to tumors in the absence of 53 BP 1. Genomic instability in cells expressing RING ‐less BRCA 1 correlates with the loss of BARD 1 and a defect in restart of replication forks after hydroxyurea treatment, suggesting a role of BRCA 1– BARD 1 in genomic integrity that is independent of RAD 51 loading.