Break-induced telomere synthesis underlies alternative telomere maintenance

Nature. 2016 Nov 3;539(7627):54-58. doi: 10.1038/nature20099. Epub 2016 Oct 19.

Abstract

Homology-directed DNA repair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening of telomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10-15% of human cancers. How DNA damage induces assembly and execution of a DNA replication complex (break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood. Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome, which underlies ALT telomere maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. Proliferating cell nuclear antigen (PCNA) loading by replication factor C (RFC) acts as the initial sensor of telomere damage to establish predominance of DNA polymerase δ (Pol δ) through its POLD3 subunit. Break-induced telomere synthesis requires the RFC-PCNA-Pol δ axis, but is independent of other canonical replisome components, ATM and ATR, or the homologous recombination protein Rad51. Thus, the inception of telomere damage recognition by the break-induced replisome orchestrates homology-directed telomere maintenance.

Publication types

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

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded*
  • DNA Damage
  • DNA Polymerase III / metabolism
  • DNA Repair
  • DNA Replication*
  • DNA-Directed DNA Polymerase / metabolism
  • Humans
  • Multienzyme Complexes / metabolism
  • Neoplasms / enzymology
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Proliferating Cell Nuclear Antigen / metabolism
  • Replication Protein C / metabolism
  • Sequence Homology
  • Telomere / metabolism*
  • Telomere Homeostasis*

Substances

  • Multienzyme Complexes
  • Proliferating Cell Nuclear Antigen
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • DNA synthesome
  • POLD3 protein, human
  • DNA Polymerase III
  • DNA-Directed DNA Polymerase
  • Replication Protein C