Abstract
ABSTRACTThe protein product of the breast and ovarian cancer gene, BRCA1, is part of an obligate heterodimer with BARD1. Together these RING bearing proteins act as an E3 ubiquitin ligase. Several functions have been attributed to BRCA1 that contribute to genome integrity but which of these, if any, require this enzymatic function was unclear. Here we review recent studies clarifying the role of BRCA1 E3 ubiquitin ligase in DNA repair. Perhaps the most surprising finding is the narrow range of BRCA1 functions this activity relates to. Remarkably ligase activity promotes chromatin remodelling and 53BP1 positioning through the remodeller SMARCAD1, but the activity is dispensable for the cellular survival in response to cisplatin or replication stressing agents. Implications for therapy response and tumor susceptibility are discussed.
Highlights
The BRCA1 protein plays several roles in genome stability: including check-point promotion, DNA crosslink repair, replication fork stability and DNA doublestrand break (DSB) repair
In addition it aids RAD51 loading through interaction with PALB2-BRCA2.3,4,5 In the absence of BRCA1, DSBs are repaired by toxic non-homologous end joining (NHEJ).[6]
Consistent with a defect in these foci signifying reduced ssDNA and Rad51-filament formation respectively, we found that the lengths of BrdU labeled ssDNA, used as a direct measure of resection lengths, were shortened in cells expressing ligase defective BRCA1-BARD1
Summary
The BRCA1 protein plays several roles in genome stability: including check-point promotion, DNA crosslink repair, replication fork stability and DNA doublestrand break (DSB) repair.
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