Shelterin-Mediated Telomere Protection

Annu Rev Genet. 2018 Nov 23;52:223-247. doi: 10.1146/annurev-genet-032918-021921. Epub 2018 Sep 12.

Abstract

For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3' overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.

Keywords: DNA damage signaling; DNA repair; DNA replication; shelterin; t-loop; telomere.

Publication types

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

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Chromosomes
  • DNA Breaks, Double-Stranded
  • DNA Damage / genetics
  • DNA End-Joining Repair
  • DNA Repair / genetics*
  • Humans
  • Mice
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Recombinational DNA Repair / genetics*
  • Telomere / genetics*
  • Telomeric Repeat Binding Protein 2 / genetics*

Substances

  • TRF2 protein, mouse
  • Telomeric Repeat Binding Protein 2
  • Poly (ADP-Ribose) Polymerase-1
  • Ataxia Telangiectasia Mutated Proteins