title: SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age.
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.
authors.affiliation: Department of Biology, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Van Meter
authors.affiliation: Department of Biology, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Mehr
authors.initials: M
authors.lastname: Kashyap
authors.affiliation: Department of Biology, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Sarallah
authors.initials: S
authors.lastname: Rezazadeh
authors.affiliation: Department of Biology, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Geneva
authors.affiliation: Department of Biology, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Morello
authors.affiliation: Department of Biology, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Seluanov
authors.affiliation: Department of Biology, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D006570:Heterochromatin / Q000378:metabolism; D047468:Immunoprecipitation; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008156:Luciferases; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D013447:Sulfites; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D017931:DNA Primers; D006570:Heterochromatin; D009687:Nuclear Proteins; D012097:Repressor Proteins; D013447:Sulfites; D008156:Luciferases; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28; C501860:Sirt6 protein, mouse; D037761:Sirtuins; C042345:hydrogen sulfite