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. Author manuscript; available in PMC: 2013 Apr 27.
Published in final edited form as: Mol Cell. 2012 Mar 22;46(2):125–135. doi: 10.1016/j.molcel.2012.02.015

Figure 6. Model for repair of DNA double-strand breaks (DSBs) induced by PARP inhibitor or DNA cross-linking agents.

Figure 6

(a) Treatment with PARP inhibitor stabilizes spontaneous DNA single-strand breaks, which are converted to DSBs during DNA replication (Bryant et al., 2005; Farmer et al., 2005). (b) DNA DSBs can be repaired either by NHEJ or HR. (c) 5′ – 3′ exonuclease resection commits repair to the error-free HR pathway. 53BP1 antagonizes double-strand break resection. (d) Ku70/80 can potentially join the DSB to a second DNA end present in the cells to cause chromosome rearrangements. (e) Treatment with cisplatin or MMC generates interstrand DNA cross-links. (f) Interstrand cross-links cause replication fork stalling and collapse. Accumulation of FANCI/D2, dependent on BRCA1, recruits endonucleases that cut DNA on either side of the interstrand cross-link to generate a double-strand break (g). (h) Trans-lesion synthesis (TLS) and (i) nucleotide excision repair (NER) re-generate duplex DNA on one sister chromatid, enabling homology-dependent repair of the DNA DSB. (j) Aberrant joining mediated by Ku70/80-competes with normal repair and can potentially generate chromosome rearrangements leading to cancer or cell death.