Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.
Mol Cell
; 81(4): 767-783.e11, 2021 02 18.
Article
em En
| MEDLINE
| ID: mdl-33333017
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 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Nucleossomos
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Poli(ADP-Ribose) Polimerases
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DNA Helicases
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Montagem e Desmontagem da Cromatina
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Proteínas de Ligação a DNA
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Proteínas de Neoplasias
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Neoplasias Experimentais
Limite:
Animals
Idioma:
En
Revista:
Mol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Reino Unido