Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

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