SET8 methyltransferase activity during the DNA double-strand break response is required for recruitment of 53BP1

Stanimir Dulev, Johnny Tkach, Sichun Lin, Nizar N Batada (Lead Author)

Research output: Contribution to journalArticlepeer-review

Abstract

DNA double-strand breaks (DSBs) activate a signaling pathway known as the DNA damage response (DDR) which via protein-protein interactions and post-translational modifications recruit signaling proteins, such as 53BP1, to chromatin flanking the lesion. Depletion of the SET8 methyltransferase prevents accumulation of 53BP1 at DSBs; however, this phenotype has been attributed to the role of SET8 in generating H4K20 methylation across the genome, which is required for 53BP1 binding to chromatin, prior to DNA damage. Here, we report that SET8 acts directly at DSBs during the DNA damage response (DDR). SET8 accumulates at DSBs and is enzymatically active at DSBs. Depletion of SET8 just prior to the induction of DNA damage abrogates 53BP1's accumulation at DSBs, suggesting that SET8 acts during DDR. SET8's occupancy at DSBs is regulated by histone deacetylases (HDACs). Finally, SET8 is functionally required for efficient repair of DSBs specifically via the non-homologous end-joining pathway (NHEJ). Our findings reveal that SET8's active role during DDR at DSBs is required for 53BP1's accumulation.

Original languageEnglish
Pages (from-to)1163-1174
Number of pages12
JournalEMBO Reports
Volume15
Issue number11
Early online date24 Sept 2014
DOIs
Publication statusPublished - 1 Nov 2014

Keywords / Materials (for Non-textual outputs)

  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair
  • HEK293 Cells
  • Histone Deacetylases
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Protein Binding
  • Protein Transport
  • Tumor Suppressor p53-Binding Protein 1
  • Epigenetic
  • Chromatin
  • Methylation
  • Ubiquitin
  • DNA damage
  • laser microirradiation

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