The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair

Sofia Henriksson, Hanif Rassoolzadeh, Elisabeth Hedström, Christos Coucoravas, Alexander Julner, Michael Goldstein, Gabriela Imreh, Boris Zhivotovsky, Michael B. Kastan, Thomas Helleday, Marianne Farnebo

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The WD40 domain-containing protein WRAP53β (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, premature aging, and neurodegeneration. Here, we identify WRAP53β as an essential regulator of DNA double-strand break (DSB) repair. WRAP53β rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1-dependent manner. We show that WRAP53β targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage. Simultaneous binding of MDC1 and RNF8 to the highly conserved WD40 scaffold domain of WRAP53β facilitates their interaction and accumulation of RNF8 at DSBs. In this manner, WRAP53β controls proper ubiquitylation at DNA damage sites and the downstream assembly of 53BP1, BRCA1, and RAD51. Furthermore, we reveal that knockdown of WRAP53β impairs DSB repair by both homologous recombination (HR) and nonhomologous end-joining (NHEJ), causes accumulation of spontaneous DNA breaks, and delays recovery from radiation-induced cell cycle arrest. Our findings establish WRAP53β as a novel regulator of DSB repair by providing a scaffold for DNA repair factors.

Original languageEnglish
Pages (from-to)2736-2738
Number of pages3
JournalGenes and Development
Volume28
Issue number24
DOIs
StatePublished - Dec 15 2014

Keywords

  • DNA repair
  • MDC1
  • RNF8 E3 ligase
  • Ubiquitin
  • WD40 scaffold
  • WRAP53β

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