Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.

Hewitt G., Borel V., Segura-Bayona S., Takaki T., Ruis P., Bellelli R., Lehmann LC., Sommerova L., Vancevska A., Tomas-Loba A., Zhu K., Cooper C., Fugger K., Patel H., Goldstone R., Schneider-Luftman D., Herbert E., Stamp G., Brough R., Pettitt S., Lord CJ., West SC., Ahel I., Ahel D., Chapman JR., Deindl S., Boulton SJ.

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.

DOI

10.1016/j.molcel.2020.12.006

Type

Journal article

Journal

Mol Cell

Publication Date

18/02/2021

Volume

81

Pages

767 - 783.e11

Keywords

ALC1, BRCAs, DNA damage repair, DNA gycosylases, PARPs, base excsion repair, chromatin remodeler, homologous recombination defieciency, poly(ADP)-ribosylation, synthetic lethality, Animals, Chromatin Assembly and Disassembly, DNA Helicases, DNA Replication, DNA-(Apurinic or Apyrimidinic Site) Lyase, DNA-Binding Proteins, Homologous Recombination, Mice, Mice, Knockout, Neoplasm Proteins, Neoplasms, Experimental, Nucleosomes, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases

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