Abstract
Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.
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•Loss of ALC1 nucleosome remodeling confers PARPi, MMS, and formyl-dU sensitivity•ALC1 is required after lesion excision by DNA glycosylases prior to APEX1•Loss of ALC1 is synthetic lethal with homologous recombination deficiency (HRD)•Endogenous alkylated base damage is a source of synthetic lethality with HRD
Hewitt et al. report that loss of the chromatin-remodeling enzyme ALC1 leads to persistent BER intermediates and a critical dependency on HR for repair. Combined loss of ALC1 and HR is synthetic lethal, which can be partially rescued by blocking excision of endogenous alkylation damage by the glycosylase MPG.