Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.
Animals
Chromatin Assembly and Disassembly
DNA Helicases
/ genetics
DNA Replication
/ drug effects
DNA-(Apurinic or Apyrimidinic Site) Lyase
/ genetics
DNA-Binding Proteins
/ genetics
Homologous Recombination
/ drug effects
Mice
Mice, Knockout
Neoplasm Proteins
/ antagonists & inhibitors
Neoplasms, Experimental
/ genetics
Nucleosomes
/ genetics
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Poly(ADP-ribose) Polymerases
/ genetics
ALC1
BRCAs
DNA damage repair
DNA gycosylases
PARPs
base excsion repair
chromatin remodeler
homologous recombination defieciency
poly(ADP)-ribosylation
synthetic lethality
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 02 2021
18 02 2021
Historique:
received:
11
05
2020
revised:
09
11
2020
accepted:
03
12
2020
pubmed:
18
12
2020
medline:
3
3
2021
entrez:
17
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33333017
pii: S1097-2765(20)30898-4
doi: 10.1016/j.molcel.2020.12.006
pmc: PMC7895907
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Neoplasm Proteins
0
Nucleosomes
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
DNA Helicases
EC 3.6.4.-
Chd1l protein, mouse
EC 3.6.4.12
Apex1 protein, mouse
EC 4.2.99.18
DNA-(Apurinic or Apyrimidinic Site) Lyase
EC 4.2.99.18
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
767-783.e11Subventions
Organisme : Medical Research Council
ID : FC0010048
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C52690/A19270
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R007195/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : FC0010048
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C35050/A22284
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 090532/Z/09/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC0010048
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 16304
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 210634
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration Of Interests G.H. and S.J.B are inventors on a patent derived from this work. S.J.B. is also scientific co-founder and VP Science Strategy at Artios Pharma Ltd., Babraham Research Campus, Cambridge, UK. The authors declare no other competing interests.
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