Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.
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Date
2021-02-18Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Research team
Gene Function
Gene Function
Language
eng
Date accepted
2020-12-03
License start date
2020-12-15
Citation
Molecular cell, 2020
Publisher
CELL PRESS