Article

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

  • Nature Communications 5, Article number: 5011 (2014)
  • doi:10.1038/ncomms6011
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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.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health to M.V.M. and V.G., and grants from the Ellison Medical foundation to V.G. and A.S.

Author information

Affiliations

  1. Department of Biology, University of Rochester, Rochester, New York 14627, USA

    • Michael Van Meter
    • , Mehr Kashyap
    • , Sarallah Rezazadeh
    • , Anthony J. Geneva
    • , Timothy D. Morello
    • , Andrei Seluanov
    •  & Vera Gorbunova

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Contributions

M.V.M., A.S. and V.G. designed the study, analysed the data and wrote the manuscript. M.V.M. performed qRT–PCR, ChIP, transfection experiments and in vitro experiments. M.K. demonstrated the requirement of KAP1 for SIRT6-induced silencing of L1. S.R. performed micrococcal nuclease assays and ChIP in mouse tissue. A.J.G. performed bioinformatics analysis. T.D.M. performed PARP1 experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Andrei Seluanov or Vera Gorbunova.

Supplementary information

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