SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclease, and Rad9-Rad1-Hus1 checkpoint clamp

BMC Mol Biol. 2015 Jun 11;16:12. doi: 10.1186/s12867-015-0041-9.


Background: SIRT6, a member of the NAD(+)-dependent histone/protein deacetylase family, regulates genomic stability, metabolism, and lifespan. MYH glycosylase and APE1 are two base excision repair (BER) enzymes involved in mutation avoidance from oxidative DNA damage. Rad9-Rad1-Hus1 (9-1-1) checkpoint clamp promotes cell cycle checkpoint signaling and DNA repair. BER is coordinated with the checkpoint machinery and requires chromatin remodeling for efficient repair. SIRT6 is involved in DNA double-strand break repair and has been implicated in BER. Here we investigate the direct physical and functional interactions between SIRT6 and BER enzymes.

Results: We show that SIRT6 interacts with and stimulates MYH glycosylase and APE1. In addition, SIRT6 interacts with the 9-1-1 checkpoint clamp. These interactions are enhanced following oxidative stress. The interdomain connector of MYH is important for interactions with SIRT6, APE1, and 9-1-1. Mutagenesis studies indicate that SIRT6, APE1, and Hus1 bind overlapping but different sequence motifs on MYH. However, there is no competition of APE1, Hus1, or SIRT6 binding to MYH. Rather, one MYH partner enhances the association of the other two partners to MYH. Moreover, APE1 and Hus1 act together to stabilize the MYH/SIRT6 complex. Within human cells, MYH and SIRT6 are efficiently recruited to confined oxidative DNA damage sites within transcriptionally active chromatin, but not within repressive chromatin. In addition, Myh foci induced by oxidative stress and Sirt6 depletion are frequently localized on mouse telomeres.

Conclusions: Although SIRT6, APE1, and 9-1-1 bind to the interdomain connector of MYH, they do not compete for MYH association. Our findings indicate that SIRT6 forms a complex with MYH, APE1, and 9-1-1 to maintain genomic and telomeric integrity in mammalian cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cell Cycle Checkpoints*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Chromatin / genetics
  • DNA / metabolism*
  • DNA Glycosylases / genetics
  • DNA Glycosylases / metabolism
  • DNA Repair*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism
  • Exonucleases / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Telomere / metabolism


  • Cell Cycle Proteins
  • Chromatin
  • rad9 protein
  • DNA
  • Sirt6 protein, mouse
  • Exonucleases
  • DNA Glycosylases
  • mutY adenine glycosylase
  • SIRT6 protein, human
  • Sirtuins
  • DNA-(Apurinic or Apyrimidinic Site) Lyase