Abstract 3956: BRCA1 chromatin dissociation induced by oncogene activation promotes formation of senescence-associated heterochromatin foci and senescence via chromatin remodeling factor BRG1

Abstract

Abstract Background: Cellular senescence is a state of irreversible cell growth arrest that is an important tumor suppression mechanism in vivo. Activation of oncogenes such as Ras in primary mammalian cells typically triggers senescence and formation of senescence-associated heterochromatin foci (SAHF) that contributes to senescence-associated cell cycle exit. We have previously showed that dissociation of BRCA1 from chromatin induced by oncogenic Ras plays a key role in promoting cellular senescence by driving SAHF formation. However, the mechanism by which BRCA1 chromatin dissociation promotes SAHF formation and senescence remains to be determined. BRG1 is an ATP dependent SWI/SNF chromatin-remodeling factor that interacts with BRCA1. Components of SWI/SNF complex including BRG1 are often deregulated in human cancer. Here we examined the role of BRG1 in regulating formation of SAHF trigged by BRCA1 chromatin dissociation induced by oncogenic Ras. Results: We discovered that the interaction between BRG1 and BRCA1 is disrupted during oncogenic RAS induced senescence. Interestingly, BRG1 accumulates in chromatin fraction while BRCA1 becomes dissociated from chromatin. Notably, BRG1 knockdown suppresses formation of SAHF and senescence, while has no effects on BRCA1 chromatin dissociation in Ras-infected cells, suggesting that BRG1 functions downstream of BRCA1 chromatin dissociation in promoting SAHF formation and senescence. Indeed, BRG1 knockdown is sufficient to inhibit SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence. Notably, senescence induced by BRG1 overexpression is independent of DNA damage response, further supporting the idea that BRG1 functions downstream of BRCA1 chromatin dissociation during Ras induced senescence. Mechanistically, chromatin immunoprecipitation analysis revealed that, in Ras-expressing or BRCA1 knockdown cells, there is an increased association of BRG1 with the promoters of p16INK4a and p21CIP, both of which are key regulators of SAHF formation and senescence. Significance: These studies revealed the molecular underpinning by which BRCA1 chromatin dissociation promotes SAHF formation and senescence. They also imply that BRG1 inactivation contributes to cancer development by suppressing cellular senescence. (R.Z. is an Ovarian Cancer Research Fund (OCRF) Liz Tilberis Scholar. This work was supported in part by a NCI FCCC-UPenn ovarian cancer SPORE (P50 CA083638) pilot project and SPORE career development award, a DOD ovarian cancer academy award (OC093420), and an OCRF program project.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3956. doi:1538-7445.AM2012-3956