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. 2013 Jan 21;200(2):187–202. doi: 10.1083/jcb.201204053

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© 2013 Grotsky et al.

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Figure 9. — Activation of CTSL-mediated degradation of 53BP1 allows BRCA1-deficient cells to overcome genomic instability and growth arrest. Depletion of BRCA1 in breast cancer cells leads to defects in HR, genomic instability, and growth arrest. Over time, BRCA1-deficient cells activate CTSL-mediated degradation of 53BP1, which rescues HR defects while inhibiting NHEJ. This allows BRCA1-deficient cells to overcome growth arrest. Inhibition of CTSL activity via treatment with vitamin D or specific inhibitors stabilizes 53BP1 protein levels and induces genomic instability in response to IR and PARPi. Furthermore, up-regulation of CTSL-mediated degradation of 53BP1 could be regulated by nuclear VDR.