requires endonucleolytic cleavage of crosslinks to initiate DSB responses. This difference and the requirement for different protein complexes during the initial recognition of each lesion could potentially account for the specific requirement for BRCA1 E3 ligase activity in the context of topoisomerase inhibitor-induced DSBs. It is interesting to note that differential requirements for BRCA1 are observed in response to poly(ADP) ribose polymerase inhibitors and ICL agents in mouse cells , thus invoking different BRCA1-dependent mechanisms to each response. While the findings from this study await further investigation in additional cell lines and in vivo systems, they have several potential clinical implications. For example, BRCA1 mutant tumors may respond differently to topisomerase inhibitors in comparison to ICL agents in a manner that depends on where the BRCA1 mutation is located. Additionally, resistance mechanisms to each agent in tumors may not be equivalent. Finally, the studies by Sato et al.  emphasize the power of genetic systems to uncover additional complexity within cellular DNA damage responses and our ever-evolving understanding of how BRCA1 contributes to this process
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