ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition.
Cell Line, Tumor
DNA Breaks, Double-Stranded
Drug Resistance, Neoplasm
E2F1 Transcription Factor
/ metabolism
HEK293 Cells
Homologous Recombination
Humans
Inhibitor of Differentiation Proteins
/ chemistry
Male
Neoplasm Proteins
/ chemistry
Poly(ADP-ribose) Polymerase Inhibitors
/ toxicity
Poly(ADP-ribose) Polymerases
/ metabolism
Prostatic Neoplasms
/ genetics
Rad51 Recombinase
/ metabolism
RecQ Helicases
/ metabolism
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
18 11 2021
18 11 2021
Historique:
accepted:
05
10
2021
revised:
23
09
2021
received:
19
07
2021
pubmed:
1
11
2021
medline:
28
12
2021
entrez:
31
10
2021
Statut:
ppublish
Résumé
The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported that ID3 loss is associated with mutational signatures linked to DNA repair defects. Here we demonstrate that ID3 exhibits a dual role to promote DNA double-strand break (DSB) repair, particularly homologous recombination (HR). ID3 interacts with the MRN complex and RECQL helicase to activate DSB repair and it facilitates RAD51 loading and downstream steps of HR. In addition, ID3 promotes the expression of HR genes in response to ionizing radiation by regulating both chromatin accessibility and activity of the transcription factor E2F1. Consistently, analyses of TCGA cancer patient data demonstrate that low ID3 expression is associated with impaired HR. The loss of ID3 leads to sensitivity of tumor cells to PARP inhibition, offering new therapeutic opportunities in ID3-deficient tumors.
Identifiants
pubmed: 34718742
pii: 6413607
doi: 10.1093/nar/gkab964
pmc: PMC8599806
doi:
Substances chimiques
E2F1 Transcription Factor
0
Inhibitor of Differentiation Proteins
0
Neoplasm Proteins
0
Poly(ADP-ribose) Polymerase Inhibitors
0
ID3 protein, human
147785-34-0
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
RecQ Helicases
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
11666-11689Commentaires et corrections
Type : ErratumIn
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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