Genes Dev.-2019-Caron-684-704.pdf (8.52 MB)
WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks
journal contribution
posted on 2023-06-07, 07:25 authored by Pierre Caron, Tibor Pankotai, Wouter W Wiegant, Maxim A X Tollenaere, Audrey Furst, Celine Bonhomme, Angela Helfricht, Anton de Groot, Albert Pastink, Alfred C O Vertegaal, Martijn S Luijsterburg, Evi SoutoglouEvi Soutoglou, Haico van AttikumDNA 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.
History
Publication status
- Published
File Version
- Published version
Journal
Genes & DevelopmentISSN
0890-9369Publisher
Cold Spring Harbor Laboratory PressExternal DOI
Issue
11-12Volume
33Page range
684-704Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-07-06First Open Access (FOA) Date
2020-07-06First Compliant Deposit (FCD) Date
2020-07-03Usage metrics
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