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https://doi.org/10.1016/j.molcel.2020.12.006
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Título: | Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD |
Fecha de publicación: | 18-feb-2021 |
Editorial: | Cell Press |
Cita bibliográfica: | Molecular Cell 81, 767–783, 2021 |
ISSN: | Print: 1097-2765 Electrónico: 1097-4164 |
Materias relacionadas: | CDU::5 - Ciencias puras y naturales::57 - Ciencias biológicas en general:577 - 577 Bioquímica. Biología molecular. Biofísica |
Resumen: | 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 attri- bute 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 em- ployed to augment existing therapeutic strategies for HRD cancers |
Autor/es principal/es: | Hewitt, Graeme Borel, Valerie Segura-Bayona, Sandra Takaki, Tohru Ruis, Phil Bellelli, Roberto Lehmann, Laura C Sommerova, Lucia Vancevska, Aleksandra Tomas-Loba, Antonia Zhu, Kang Cooper, Christopher Fugger, Kasper Patel, Harshil Goldstone, Robert Schneider-Luftman, Deborah Herbert, Ellie Stamp, Gordon Brough, Rachel Pettitt, Stephen Lord, Christopher J West, Stephen C Ahel, Ivan Ahel, Dragana Chapman, J Ross Deindl, Sebastian Boulton, Simon J |
Facultad/Departamentos/Servicios: | Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Departamento de Fisiología |
URI: | http://hdl.handle.net/10201/138806 |
DOI: | https://doi.org/10.1016/j.molcel.2020.12.006 |
Tipo de documento: | info:eu-repo/semantics/article |
Número páginas / Extensión: | 29 |
Derechos: | info:eu-repo/semantics/embargoedAccess |
Descripción: | ©2020 The Author(s). This document is the Published version of a Published Work that appeared in final form in Molecular Cell. To access the final edited and published work see https://doi.org/10.1016/j.molcel.2020.12.006 |
Aparece en las colecciones: | Artículos: Fisiología |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
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ALC1.pdf | 5,45 MB | Adobe PDF | Visualizar/Abrir Solicitar una copia |
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