Publication: Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD
Authors
Hewitt, Graeme ; Borel, Valerie ; Segura-Bayona, Sandra ; Takaki, Tohru ; Ruis, Phil ; Bellelli, Roberto ; Lehmann, Laura C ; Sommerova, Lucia ; Vancevska, Aleksandra ; Tomas-Loba, Antonia ; Zhu, Kang ; Cooper, Christopher ; Fugger, Kasper ; Patel, Harshil ; Goldstone, Robert ; Schneider-Luftman, Deborah ; Herbert, Ellie ; Stamp, Gordon ; Brough, Rachel ; Pettitt, Stephen ; Lord, Christopher J ; West, Stephen C ; Ahel, Ivan ; Ahel, Dragana ; Chapman, J Ross ; Deindl, Sebastian ; Boulton, Simon J
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Publisher
Cell Press
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DOI
https://doi.org/10.1016/j.molcel.2020.12.006
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info:eu-repo/semantics/article
Description
©2020 The Author(s). This document is the Published version of a Published Work that appeared in final form in Molecular Cell. To access the final edited and published work see
https://doi.org/10.1016/j.molcel.2020.12.006
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 attri-
bute 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 em-
ployed to augment existing therapeutic strategies for HRD cancers
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Citation
Molecular Cell 81, 767–783, 2021
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