WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks

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...

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Bibliographic Details
Published in:Genes & development 2019-06, Vol.33 (11-12), p.684-704
Main Authors: Caron, Pierre, Pankotai, Tibor, Wiegant, Wouter W, Tollenaere, Maxim A X, Furst, Audrey, Bonhomme, Celine, Helfricht, Angela, de Groot, Anton, Pastink, Albert, Vertegaal, Alfred C O, Luijsterburg, Martijn S, Soutoglou, Evi, van Attikum, Haico
Format: Article
Language:English
Subjects:
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
Life Sciences
Nuclear Proteins - metabolism
Proteasome Endopeptidase Complex - metabolism
Research Paper
RNA Polymerase II - metabolism
Transcription, Genetic
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.321943.118