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

Pierre Caron1, Tibor Pankotai2,3,4,5, Wouter W Wiegant1

  • 1Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.

Genes & Development
|May 4, 2019
PubMed

Insights

WWP2 ubiquitinates RNA polymerase II (RNAPII) to promote its eviction from DNA double-strand breaks (DSBs). This process, regulated by DNA-PK, facilitates DNA repair by clearing transcription machinery.

Area of Science:

  • Molecular Biology
  • DNA Repair
  • Gene Transcription

Background:

  • DNA double-strand breaks (DSBs) halt transcription by RNA polymerase II (RNAPII).
  • The DNA-dependent protein kinase (DNA-PK) complex mediates RNAPII eviction at DSBs, but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which DNA-PK triggers RNAPII eviction at DSBs.
  • To identify the factors involved in targeting RNAPII for eviction.

Main Methods:

  • Investigated the association of WWP2 with DNA-PK and RNAPII complexes.
  • Assessed WWP2 recruitment to DSBs.
  • Examined the ubiquitylation of RPB1 by WWP2.
  • Studied the impact of WWP2 depletion or non-ubiquitylatable RPB1 on DNA repair factor binding and DSB repair.

Main Results:

  • WWP2, a HECT E3 ubiquitin ligase, associates with DNA-PK and RNAPII and is recruited to DSBs.
  • WWP2 mediates K48-linked ubiquitylation of the RPB1 subunit of RNAPII, leading to its eviction via the proteasome.
  • Loss of WWP2 or non-ubiquitylatable RPB1 impairs the recruitment of nonhomologous end joining (NHEJ) factors and hinders DSB repair.

Conclusions:

  • WWP2 acts as a crucial E3 ligase in a DNA-PK-dependent pathway for RNAPII clearance at DSBs.
  • This RNAPII eviction mechanism promotes efficient DSB repair by preventing conflicts between transcription and NHEJ machinery.
Keywords:
DNA double-strand break repairDNA-PKRNAPII ubiquitylationWWP2 HECT E3 ubiquitin ligasetranscription silencing

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