WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks.
Cell Line, Transformed
Cell Line, Tumor
DNA Breaks, Double-Stranded
DNA End-Joining Repair
DNA-Activated Protein Kinase
/ metabolism
DNA-Directed RNA Polymerases
/ metabolism
Humans
Nuclear Proteins
/ metabolism
Proteasome Endopeptidase Complex
/ metabolism
RNA Polymerase II
/ metabolism
Transcription, Genetic
Ubiquitin-Protein Ligases
/ metabolism
Ubiquitination
DNA double-strand break repair
DNA-PK
RNAPII ubiquitylation
WWP2 HECT E3 ubiquitin ligase
transcription silencing
Journal
Genes & development
ISSN: 1549-5477
Titre abrégé: Genes Dev
Pays: United States
ID NLM: 8711660
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
22
10
2018
accepted:
25
03
2019
pubmed:
3
5
2019
medline:
4
9
2019
entrez:
4
5
2019
Statut:
ppublish
Résumé
DNA double-strand breaks (DSBs) at RNA polymerase II (RNAPII) transcribed genes lead to inhibition of transcription. The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in transcription inhibition at DSBs by stimulating proteasome-dependent eviction of RNAPII at these lesions. How DNA-PK triggers RNAPII eviction to inhibit transcription at DSBs remains unclear. Here we show that the HECT E3 ubiquitin ligase WWP2 associates with components of the DNA-PK and RNAPII complexes and is recruited to DSBs at RNAPII transcribed genes. In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. The lack of WWP2 or expression of nonubiquitylatable RPB1 abrogates the binding of nonhomologous end joining (NHEJ) factors, including DNA-PK and XRCC4/DNA ligase IV, and impairs DSB repair. These findings suggest that WWP2 operates in a DNA-PK-dependent shutoff circuitry for RNAPII clearance that promotes DSB repair by protecting the NHEJ machinery from collision with the transcription machinery.
Identifiants
pubmed: 31048545
pii: gad.321943.118
doi: 10.1101/gad.321943.118
pmc: PMC6546063
doi:
Substances chimiques
Nuclear Proteins
0
WWP2 protein, human
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
DNA-Activated Protein Kinase
EC 2.7.11.1
PRKDC protein, human
EC 2.7.11.1
RNA Polymerase II
EC 2.7.7.-
DNA-Directed RNA Polymerases
EC 2.7.7.6
POLR2A RNA polymerase, human
EC 2.7.7.6
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
684-704Informations de copyright
© 2019 Caron et al.; Published by Cold Spring Harbor Laboratory Press.
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