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

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posted on 30.03.2021, 13:32 by Graeme Hewitt, Valerie Borel, Sandra Segura-Bayona, Tohru Takaki, Phil Ruis, Roberto Bellelli, Laura C Lehmann, Lucia Sommerova, Aleksandra Vancevska, Antonia Tomas-Loba, Kang Zhu, Christopher Cooper, Kasper Fugger, Harshil Patel, Robert Goldstone, Deborah Schneider-Luftman, Ellie Herbert, Gordon Stamp, Rachel Brough, Stephen Pettitt, Christopher J Lord, Stephen C West, Ivan Ahel, Dragana Ahel, J Ross Chapman, Sebastian Deindl, Simon J Boulton
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.

Funding

Crick (Grant ID: 10048, Grant title: Boulton FC001048) Crick (Grant ID: 10212, Grant title: West FC001212) European Research Council (Grant ID: 742437 - TelMetab, Grant title: ERC 742437 - TelMetab) Crick (Grant ID: 10001, Grant title: STP Advanced Sequencing) Crick (Grant ID: 10002, Grant title: STP Bioinformatics & Biostatistics)

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