The Oncogenic Helicase ALC1 Regulates PARP Inhibitor Potency by Trapping PARP2 at DNA Breaks.
Cell Line, Tumor
DNA Breaks, Single-Stranded
DNA Helicases
/ genetics
DNA-Binding Proteins
/ genetics
Humans
Neoplasms
/ enzymology
Poly (ADP-Ribose) Polymerase-1
/ genetics
Poly(ADP-ribose) Polymerase Inhibitors
/ metabolism
Poly(ADP-ribose) Polymerases
/ genetics
Proto-Oncogene Proteins
/ genetics
ALC1
BRCA
DNA damage
PARP inhibitors
PARP trapping
PARP2
cancer target
chromatin remodeling
helicases
synthetic lethality
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
03 12 2020
03 12 2020
Historique:
received:
13
05
2020
revised:
27
08
2020
accepted:
04
10
2020
entrez:
4
12
2020
pubmed:
5
12
2020
medline:
17
12
2020
Statut:
ppublish
Résumé
The anti-tumor potency of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) has been linked to trapping of PARP1 on damaged chromatin. However, little is known about their impact on PARP2, an isoform with overlapping functions at DNA lesions. Whether the release of PARP1/2 from DNA lesions is actively catalyzed by molecular machines is also not known. We found that PARPis robustly trap PARP2 and that the helicase ALC1 (CHD1L) is strictly required for PARP2 release. Catalytic inactivation of ALC1 quantitatively traps PARP2 but not PARP1. ALC1 manipulation impacts the response to single-strand DNA breaks through PARP2 trapping, potentiates PARPi-induced cancer cell killing, and mediates synthetic lethality upon BRCA deficiency. The chromatin remodeler ALC1 actively drives PARP2 turnover from DNA lesions, and PARP2 contributes to the cellular responses of PARPi. This suggests that disrupting the ATP-fueled remodeling forces of ALC1 might enable therapies that selectively target the DNA repair functions of PARPs in cancer.
Identifiants
pubmed: 33275888
pii: S1097-2765(20)30692-4
doi: 10.1016/j.molcel.2020.10.009
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Proto-Oncogene Proteins
0
PARP1 protein, human
EC 2.4.2.30
PARP2 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
DNA Helicases
EC 3.6.4.-
CHD1L protein, human
EC 3.6.4.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
862-875.e6Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests A.S. and A.G.L. are co-founders and shareholders of Eisbach Bio, a biotech developing small-molecule inhibitors targeting helicases.