Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.
Animals
BRCA1 Protein
/ genetics
Biopsy
CRISPR-Cas Systems
Cell Line
Cell Nucleus
/ metabolism
Cell Proliferation
Chromosome Aberrations
DNA Damage
DNA Ligase ATP
/ genetics
DNA, Single-Stranded
Female
Humans
Lentivirus
/ genetics
MRE11 Homologue Protein
/ genetics
Mammary Neoplasms, Animal
Mice
Mutation
Ovarian Neoplasms
/ metabolism
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Poly-ADP-Ribose Binding Proteins
/ genetics
RNA, Small Interfering
/ metabolism
Transgenes
Triple Negative Breast Neoplasms
/ metabolism
Tumor Suppressor p53-Binding Protein 1
/ genetics
53BP1
BRCA1
DNA damage response
DNA ligase III
PARP1, PARP inhibitor
drug resistance
replication fork
ssDNA gaps
vulnerabilities
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 11 2021
18 11 2021
Historique:
received:
28
09
2020
revised:
20
07
2021
accepted:
01
09
2021
pubmed:
24
9
2021
medline:
8
1
2022
entrez:
23
9
2021
Statut:
ppublish
Résumé
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.
Identifiants
pubmed: 34555355
pii: S1097-2765(21)00739-5
doi: 10.1016/j.molcel.2021.09.005
pmc: PMC9098260
mid: NIHMS1796493
pii:
doi:
Substances chimiques
BRCA1 Protein
0
Brca1 protein, mouse
0
DNA, Single-Stranded
0
Mre11a protein, mouse
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Poly-ADP-Ribose Binding Proteins
0
RNA, Small Interfering
0
Trp53bp1 protein, mouse
0
Tumor Suppressor p53-Binding Protein 1
0
MRE11 Homologue Protein
EC 3.1.-
DNA Ligase ATP
EC 6.5.1.1
Lig3 protein, mouse
EC 6.5.1.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4692-4708.e9Subventions
Organisme : NCI NIH HHS
ID : R01 CA254037
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests G.C.M.S. is an employee and shareholder of ArtiosPharma Ltd. and of AstraZeneca PLC. All other authors declare no competing interests.
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