title: Oncogenic RAS regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence.
abstract: Here, we report a cell-intrinsic mechanism by which oncogenic RAS promotes senescence while predisposing cells to senescence bypass by allowing for secondary hits. We show that oncogenic RAS inactivates the BRCA1 DNA repair complex by dissociating BRCA1 from chromatin. This event precedes senescence-associated cell cycle exit and coincides with the accumulation of DNA damage. Downregulation of BRIP1, a physiological partner of BRCA1 in the DNA repair pathway, triggers BRCA1 chromatin dissociation. Conversely, ectopic BRIP1 rescues BRCA1 chromatin dissociation and suppresses RAS-induced senescence and the DNA damage response. Significantly, cells undergoing senescence do not exhibit a BRCA1-dependent DNA repair response when exposed to DNA damage. Overall, our study provides a molecular basis by which oncogenic RAS promotes senescence. Because DNA damage has the potential to produce additional "hits" that promote senescence bypass, our findings may also suggest one way a small minority of cells might bypass senescence and contribute to cancer development.
authors.affiliation: Women's Cancer Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tu
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Aird
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Bitler
authors.forename: Jasmine P
authors.initials: JP
authors.lastname: Nicodemus
authors.forename: Neil
authors.initials: N
authors.lastname: Beeharry
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Yen
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D019398:Genes, BRCA1; D011905:Genes, ras; D006801:Humans; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C000618935:BRIP1 protein, human; D020365:RNA Helicases