2026-07-21T15:51:51Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/133472024-09-27T08:33:49Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Hewitt, Graeme author Borel, Valerie author Segura-Bayona, Sandra author Takaki, Tohru author Ruis, Phil author Bellelli, Roberto author Lehmann, Laura C author Sommerova, Lucia author Vancevska, Aleksandra author Tomas-Loba, Antonia author Zhu, Kang author Cooper, Christopher author Fugger, Kasper author Patel, Harshil author Goldstone, Robert author Schneider-Luftman, Deborah author Herbert, Ellie author Stamp, Gordon author Brough, Rachel author Pettitt, Stephen author Lord, Christopher J author West, Stephen C author Ahel, Ivan author Ahel, Dragana author Chapman, J Ross author Deindl, Sebastian author Boulton, Simon J author 2021-02 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. Mol Cell. 2021; 81:767-783.e11 10.1016/j.molcel.2020.12.006 1097-4164 1097-2765 Molecular cell 33333017 http://hdl.handle.net/20.500.12105/13347 Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.