DNA double-strand break-derived RNA drives TIRR/53BP1 complex dissociation

Cell Rep. 2022 Oct 25;41(4):111526. doi: 10.1016/j.celrep.2022.111526.

Abstract

Tudor-interacting repair regulator (TIRR) is an RNA-binding protein and a negative regulator of the DNA-repair factor p53-binding protein 1 (53BP1). In non-damage conditions, TIRR is bound to 53BP1. After DNA damage, TIRR and 53BP1 dissociate, and 53BP1 binds the chromatin at the double-strand break (DSB) to promote non-homologous end joining (NHEJ)-mediated repair. However, the exact mechanistic details of this dissociation after damage are unknown. Increasing evidence has implicated RNA as a crucial factor in the DNA damage response (DDR). Here, we show that RNA can separate TIRR/53BP1. Specifically, RNA with a hairpin secondary structure, transcribed at the DSB by RNA polymerase II (RNAPII), promotes TIRR/53BP1 complex separation. This hairpin RNA binds to the same residues on TIRR as 53BP1. Our results uncover a role of DNA-damage-derived RNA in modulating a protein-protein interaction and contribute to our understanding of DSB repair.

Keywords: 53BP1; CP: Molecular biology; DARTs; DNA damage; FISH-PLA; NHEJ; RNA; TIRR; dilncRNA; double-strand breaks; hairpin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin
  • DNA / metabolism
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair
  • DNA Repair
  • Protein Binding
  • RNA Polymerase II / metabolism
  • RNA* / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / metabolism

Substances

  • RNA
  • RNA Polymerase II
  • Tumor Suppressor Protein p53
  • Tumor Suppressor p53-Binding Protein 1
  • Chromatin
  • RNA-Binding Proteins
  • DNA