Article

Oncogenic Ras Regulates BRIP1 Expression to Induce Dissociation of BRCA1 from Chromatin, Inhibit DNA Repair, and Promote Senescence

Women's Cancer Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Developmental Cell (Impact Factor: 9.71). 11/2011; 21(6):1077-91. DOI: 10.1016/j.devcel.2011.10.010
Source: PubMed

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.

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    • "Diminished sumoylation of chromatinassociated substrates in this fraction is therefore most likely to be masked by the presence of the PML NBs and other insoluble SUMO susbtrates. However, in agreement with previous reports (Tu et al. 2011), a reduction in BRCA1 is seen in the nuclear pellet fraction of the senescent cells (Fig. 7C). Thus, although global sumoylation increases in senescent cells, the ChIP-seq experiments reveal a general loss of sumoylated chromatin-associated proteins in the senescent state. "
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    Full-text · Article · Jul 2013 · Genome Research
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    • "Immunofluorescence, BrdU Labeling, and SA-b-Gal Staining Immunofluorescence staining and BrdU labeling were performed as described previously using antibodies described above (Tu et al., 2011; Zhang et al., 2005, 2007a, 2007b). SA-b-gal staining was performed as previously described (Dimri et al., 1995). "
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    Full-text · Article · Apr 2013 · Cell Reports
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    • "The human breast cancer cell line MCF7, which is BRCA1 and 53BP1 proficient, was depleted of BRCA1 via lentiviral transduction with shRNAs (Fig. 1 A and Fig. S1 A). As previously shown in human fibroblasts (Tu et al., 2011), depletion of BRCA1 in MCF7 cells induces growth arrest (Fig. 1 B). BRCA1-deficient cells did not show differences in the levels of 53BP1 or CTSL proteins immediately after growth arrest (Fig. 1 C). "
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