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 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.
Mesh Terms:
Cell Line, Transformed, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA-Activated Protein Kinase, DNA-Directed RNA Polymerases, Humans, Nuclear Proteins, Proteasome Endopeptidase Complex, RNA Polymerase II, Transcription, Genetic, Ubiquitin-Protein Ligases, Ubiquitination
Cell Line, Transformed, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA-Activated Protein Kinase, DNA-Directed RNA Polymerases, Humans, Nuclear Proteins, Proteasome Endopeptidase Complex, RNA Polymerase II, Transcription, Genetic, Ubiquitin-Protein Ligases, Ubiquitination
Genes Dev.
Date: Dec. 01, 2018
PubMed ID: 31048545
View in: Pubmed Google Scholar
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