SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age

Nat Commun. 2014 Sep 23:5:5011. doi: 10.1038/ncomms6011.

Abstract

L1 retrotransposons are an abundant class of transposable elements that pose a threat to genome stability and may have a role in age-related pathologies such as cancer. Recent evidence indicates that L1s become more active in somatic tissues during the course of ageing; however the mechanisms underlying this phenomenon remain unknown. Here we report that the longevity regulating protein, SIRT6, is a powerful repressor of L1 activity. Specifically, SIRT6 binds to the 5'-UTR of L1 loci, where it mono-ADP ribosylates the nuclear corepressor protein, KAP1, and facilitates KAP1 interaction with the heterochromatin factor, HP1α, thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin. During the course of ageing, and also in response to DNA damage, however, we find that SIRT6 is depleted from L1 loci, allowing the activation of these previously silenced retroelements.

Publication types

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

MeSH terms

  • Aging / physiology*
  • Animals
  • Chromatin Immunoprecipitation
  • DNA Primers / genetics
  • Heterochromatin / metabolism
  • Immunoprecipitation
  • Long Interspersed Nucleotide Elements / genetics*
  • Luciferases
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Repressor Proteins / metabolism*
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Stress, Physiological / physiology*
  • Sulfites
  • Tripartite Motif-Containing Protein 28

Substances

  • DNA Primers
  • Heterochromatin
  • Nuclear Proteins
  • Repressor Proteins
  • Sulfites
  • Luciferases
  • Trim28 protein, mouse
  • Tripartite Motif-Containing Protein 28
  • Sirt6 protein, mouse
  • Sirtuins
  • hydrogen sulfite