Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells.
Animals
Chromatin
/ metabolism
DNA Breaks, Double-Stranded
DNA Repair
DNA Topoisomerases, Type II
/ metabolism
DNA, Ribosomal
/ metabolism
DNA-Binding Proteins
/ genetics
Mice
Mouse Embryonic Stem Cells
/ metabolism
Poly-ADP-Ribose Binding Proteins
/ metabolism
Promoter Regions, Genetic
Signal Transduction
Transcription Initiation Site
Transcription, Genetic
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 08 2021
11 08 2021
Historique:
received:
12
06
2019
accepted:
20
07
2021
entrez:
12
8
2021
pubmed:
13
8
2021
medline:
24
8
2021
Statut:
epublish
Résumé
Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 mediates hypertranscription in pluripotent cells but its mechanism of action remains poorly understood. Here we report a novel role for Chd1 in protecting genome integrity at promoter regions by preventing DNA double-stranded break (DSB) accumulation in ES cells. Chd1 interacts with several DNA repair factors including Atm, Parp1, Kap1 and Topoisomerase 2β and its absence leads to an accumulation of DSBs at Chd1-bound Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1 KO ES cells are longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin regulation, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to accumulation of endogenous DNA breaks, with important implications for developmental and cancer biology.
Identifiants
pubmed: 34381042
doi: 10.1038/s41467-021-25088-3
pii: 10.1038/s41467-021-25088-3
pmc: PMC8357957
doi:
Substances chimiques
Chd1 protein, mouse
0
Chromatin
0
DNA, Ribosomal
0
DNA-Binding Proteins
0
Poly-ADP-Ribose Binding Proteins
0
DNA Topoisomerases, Type II
EC 5.99.1.3
Top2b protein, mouse
EC 5.99.1.3
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
4859Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM123556
Pays : United States
Organisme : Cancer Research UK
ID : C5759/A25254
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM113014
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA163336
Pays : United States
Organisme : CIHR
ID : 420231
Pays : Canada
Organisme : NCI NIH HHS
ID : P30 CA082103
Pays : United States
Informations de copyright
© 2021. The Author(s).
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