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- W2550470554 abstract "The retinoblastoma (RB) tumor suppressor is widely recognized as a master regulator of the transcriptional program that controls entry into the S phase of the cell cycle. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin-remodelers and modifiers to the promoters of E2F target genes. Here we show that RB localizes to DNA double strand breaks (DSBs) dependent on E2F1 and ATM kinase activity. Moreover, RB promotes DNA end resection and homologous recombination, and its loss results in genome instability. RB mediates this important role in repair by recruiting the SWI/SNF chromatin remodeler BRG1 to DSBs. In agreement with these results, loss of BRG1 also results in impaired DNA end resection and HR. RB is recruited to DSBs through a DNA damage-inducible phospho-specific interaction between E2F1 and TopBP1. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1 and BRG1 to DSBs. This E2F1 mutation also impairs DNA repair, increases genomic instability and renders knock-in mice hypersensitive to IR. We uncover a novel, non-transcriptional function for RB in HR, which could contribute to genome instability associated with RB loss in human cancers and explain their sensitivity to DSB-inducing agents. This abstract is also being presented as Poster B09. Citation Format: Renier Velez-Cruz, Swarnalatha Manickavinayaham, Anup K. Biswas, Regina Weaks Clary, David G. Johnson. RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of SWI/SNF complex. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR05." @default.
- W2550470554 created "2016-11-30" @default.
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- W2550470554 date "2016-11-01" @default.
- W2550470554 modified "2023-10-16" @default.
- W2550470554 title "Abstract PR05: RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of SWI/SNF complex" @default.
- W2550470554 doi "https://doi.org/10.1158/1557-3125.cellcycle16-pr05" @default.
- W2550470554 hasPublicationYear "2016" @default.
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