TRF1 averts chromatin remodelling, recombination and replication dependent-break induced replication at mouse telomeres

Elife. 2020 Jan 14;9:e49817. doi: 10.7554/eLife.49817.

Abstract

Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that mouse telomeres lacking TRF1 undergo protein composition reorganisation associated with the recruitment of DNA damage response and chromatin remodellers. Surprisingly, mTRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for mTRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

Keywords: ALT; DNA damage response; DNA recombination; TERRA; cell biology; chromosomes; gene expression; human; mouse; replication; telomere.

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly*
  • DNA / biosynthesis
  • DNA Breaks*
  • DNA Polymerase III / metabolism
  • DNA Replication / genetics*
  • Gene Deletion
  • Humans
  • Inclusion Bodies / metabolism
  • Mice
  • Mitosis
  • Recombination, Genetic / genetics*
  • Telomere / metabolism*
  • Telomeric Repeat Binding Protein 1 / metabolism*
  • Up-Regulation / genetics

Substances

  • Cell Cycle Proteins
  • Chromatin
  • SMC5 protein, mouse
  • Telomeric Repeat Binding Protein 1
  • DNA
  • POLD3 protein, mouse
  • DNA Polymerase III