The dystonia gene THAP1 controls DNA double-strand break repair choice.
Animals
BRCA1 Protein
/ genetics
Cell Cycle Proteins
/ genetics
DNA
/ metabolism
DNA Breaks, Double-Stranded
/ drug effects
DNA End-Joining Repair
/ drug effects
DNA Repair
/ genetics
DNA-Binding Proteins
/ genetics
Dystonia
/ genetics
Female
Host Cell Factor C1
/ metabolism
Mad2 Proteins
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Poly (ADP-Ribose) Polymerase-1
/ metabolism
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Recombinational DNA Repair
/ drug effects
Telomere-Binding Proteins
/ metabolism
Tumor Suppressor p53-Binding Protein 1
/ metabolism
YY1 Transcription Factor
/ metabolism
BRCA1
SHLD1
THAP1
antibody class-switch recombination
cancer
dystonia
homologous recombination
non-homologous end joining
resection
transcriptional regulation
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
17 06 2021
17 06 2021
Historique:
received:
29
07
2020
revised:
01
02
2021
accepted:
19
03
2021
pubmed:
16
4
2021
medline:
21
7
2021
entrez:
15
4
2021
Statut:
ppublish
Résumé
The Shieldin complex shields double-strand DNA breaks (DSBs) from nucleolytic resection. Curiously, the penultimate Shieldin component, SHLD1, is one of the least abundant mammalian proteins. Here, we report that the transcription factors THAP1, YY1, and HCF1 bind directly to the SHLD1 promoter, where they cooperatively maintain the low basal expression of SHLD1, thereby ensuring a proper balance between end protection and resection during DSB repair. The loss of THAP1-dependent SHLD1 expression confers cross-resistance to poly (ADP-ribose) polymerase (PARP) inhibitor and cisplatin in BRCA1-deficient cells and shorter progression-free survival in ovarian cancer patients. Moreover, the embryonic lethality and PARPi sensitivity of BRCA1-deficient mice is rescued by ablation of SHLD1. Our study uncovers a transcriptional network that directly controls DSB repair choice and suggests a potential link between DNA damage and pathogenic THAP1 mutations, found in patients with the neurodevelopmental movement disorder adult-onset torsion dystonia type 6.
Identifiants
pubmed: 33857404
pii: S1097-2765(21)00229-X
doi: 10.1016/j.molcel.2021.03.034
pmc: PMC8985095
mid: NIHMS1772517
pii:
doi:
Substances chimiques
BRCA1 Protein
0
Cell Cycle Proteins
0
DNA-Binding Proteins
0
HCFC1 protein, human
0
Host Cell Factor C1
0
Mad2 Proteins
0
Poly(ADP-ribose) Polymerase Inhibitors
0
SHLD1 protein, human
0
THAP1 protein, mouse
0
Telomere-Binding Proteins
0
Tumor Suppressor p53-Binding Protein 1
0
YY1 Transcription Factor
0
YY1 protein, human
0
DNA
9007-49-2
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2611-2624.e10Subventions
Organisme : NINDS NIH HHS
ID : P01 NS087997
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 BC010959
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 BC010283
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010283
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS037956
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010959
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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