TOPBP1 Dpb11 plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1 Rad9

J Cell Biol. 2017 Mar 6;216(3):623-639. doi: 10.1083/jcb.201607031. Epub 2017 Feb 22.

Abstract

Genome maintenance and cancer suppression require homologous recombination (HR) DNA repair. In yeast and mammals, the scaffold protein TOPBP1Dpb11 has been implicated in HR, although its precise function and mechanism of action remain elusive. In this study, we show that yeast Dpb11 plays an antagonistic role in recombination control through regulated protein interactions. Dpb11 mediates opposing roles in DNA end resection by coordinating both the stabilization and exclusion of Rad9 from DNA lesions. The Mec1 kinase promotes the pro-resection function of Dpb11 by mediating its interaction with the Slx4 scaffold. Human TOPBP1Dpb11 engages in interactions with the anti-resection factor 53BP1 and the pro-resection factor BRCA1, suggesting that TOPBP1 also mediates opposing functions in HR control. Hyperstabilization of the 53BP1-TOPBP1 interaction enhances the recruitment of 53BP1 to nuclear foci in the S phase, resulting in impaired HR and the accumulation of chromosomal aberrations. Our results support a model in which TOPBP1Dpb11 plays a conserved role in mediating a phosphoregulated circuitry for the control of recombinational DNA repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics*
  • DNA Damage / genetics
  • DNA-Binding Proteins / genetics*
  • Fungal Proteins / genetics
  • HEK293 Cells
  • Homologous Recombination / genetics*
  • Humans
  • Nuclear Proteins / genetics*
  • Recombinational DNA Repair / genetics*
  • S Phase / genetics
  • Tumor Suppressor p53-Binding Protein 1 / genetics*
  • Yeasts

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Fungal Proteins
  • Nuclear Proteins
  • Tumor Suppressor p53-Binding Protein 1