USP3 controls BRCA1 “foci”

BRCA1, which is mutated in the familial forms of breast and ovarian cancer, plays important roles in genome stability through its participation in DNA damage response (DDR) following double-stranded breaks (DsBs). BRCA1 activates the checkpoint pathway to retard cell cycle progression and stimulates repair of the DsBs (reviewed in ref. 1). it is recruited to the damaged chromatin through an interaction with RAP80 that binds to K63 ubiquitin chain on histones H2A and γH2AX. 1 Recruitment of BRCA1 at the damaged-sites on chromatin is detected by co-immunostain-ing with γH2AX that forms microscopically visible aggregates, also known as " foci ". studies on double-stranded break repair (DsBR) provided evidence that BRCA1 is important for driving repair through homologous recom-bination (HR), mainly by antagonizing the activities of 53BP1 (reviewed in ref. 2). 53BP1 promotes DsBR through the non-homologous end-joining (NHeJ) pathway. in the absence of functional BRCA1 error-prone NHeJ pathway prevails, whereas recruitment of BRCA1 opposes the activity of 53BP1 and directs repair through the more reliable mechanism of HR. That concept was supported also by studies in mouse models in which it was shown that the embryonic defects and chro-mosomal abnormality in BRCA1-mutant mice were reversed by deletion of the 53BP1 alleles (ref. 2 and references therein). Therefore, we have gained some insights into how BRCA1 maintains genome integrity. The mechanism by which BRCA1 is recruited to the damaged chromatin has been studied extensively, because the components in that mechanism are likely to be involved in the tumor suppression pathway of BRCA1. Those studies led to the identification of 2 e3 ligases, RNF8 and RNF168, which are recruited by MDC1 at the damaged chromatin (ref. 1 and references therein). Once recruited, these ligases introduce K63 ubiquitin chains on K13/K15 residues in H2A/γH2AX. 3 The K63 ubiq-uitin chains on H2A/γH2AX are recognized by RAP80 that leads to the recruitment of BRCA1. 4 The recruitment of 53BP1 also requires ubiqui-tylation; however, the mechanism is indirect. it is thought that ubiquitylation unmasks chro-matin, exposing methylated histones recognized by the Tudor domain of 53BP1. 5 Given the critical roles of ubiquitylation in recruiting BRCA1 and 53BP1 onto the damaged chromatin, the deubiquitylating enzymes that reverse the effects of RNF8/ RNF168 have drawn a lot of attention, at least partly because of their obvious implications in oncogenesis. in that regard one study 6 demonstrated UsP44 to be involved in inhibiting recruitment of 53BP1 and RAP80 to …