2024-03-29T08:25:22Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/133472022-10-13T08:53:03Zcom_20.500.12105_2145com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2146
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
1097-2765
http://hdl.handle.net/20.500.12105/13347
33333017
10.1016/j.molcel.2020.12.006
1097-4164
Molecular cell
Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.