C1ORF112 Mediates HR Intermediates resolution in Response to DNA Interstrand Crosslinks
DNA interstrand crosslinks (ICLs) pose a major obstacle for DNA replication and transcription if left unrepaired. The cellular response to ICLs requires the coordination of various DNA repair mechanisms. Homologous recombination (HR) intermediates generated in response to ICLs, require efficient and timely conversion by structure-selective endonucleases. However, regulators that coordinate recruitment and activity of these enzymes remain elusive. Here, we designed complementary genetic screens to map the machinery involved in the response to ICLs and identified C1ORF112, an uncharacterized scaffold protein, as an indispensable factor in maintaining genome stability upon exposure to ICLs. While C1ORF112 deficiency does not disable the FA pathway, it leads to hypersensitivity to ICL-inducing compounds, accumulation of DNA damage during S/G2 phase of the cell cycle, chromosomal aberrations and elicits a unique mutational signature previously observed in HR-deficient tumors. Mechanistically, C1ORF112 is recruited to ICLs, controls MUS81 chromatin loading, and thereby ensures HR intermediates resolution. C1ORF112 deficiency in mice causes early embryonic lethality and accelerates tumor formation. Thus, C1ORF112 plays a critical role in the response to ICLs encountered during DNA replication by controlling resolution of HR intermediates.