A chromosomal SIR2 homologue with both histone NAD-dependent ADP-ribosyltransferase and deacetylase activities is involved in DNA repair in Trypanosoma brucei

EMBO J. 2003 Nov 3;22(21):5851-62. doi: 10.1093/emboj/cdg553.

Abstract

SIR2-like proteins have been implicated in a wide range of cellular events including chromosome silencing, chromosome segregation, DNA recombination and the determination of life span. We report here the molecular and functional characterization of a SIR2-related protein from the protozoan parasite Trypanosoma brucei, which we termed TbSIR2RP1. This protein is a chromosome-associated NAD-dependent enzyme which, in contrast to other known proteins of this family, catalyses both ADP-ribosylation and deacetylation of histones, particulary H2A and H2B. Under- or overexpression of TbSIR2RP1 decreased or increased, respectively, cellular resistance to DNA damage. Treatment of trypanosomal nuclei with a DNA alkylating agent resulted in a significant increase in the level of histone ADP-ribosylation and a concomitant increase in chromatin sensitivity to micrococcal nuclease. Both of these responses correlated with the level of TbSIR2RP1 expression. We propose that histone modification by TbSIR2RP1 is involved in DNA repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / toxicity
  • Animals
  • DNA Damage
  • DNA Repair / genetics
  • DNA Repair / physiology*
  • Genes, Protozoan
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • In Vitro Techniques
  • Nuclear Proteins / metabolism
  • Protozoan Proteins / metabolism*
  • Sirtuins / metabolism*
  • Substrate Specificity
  • Trypanosoma brucei brucei / drug effects
  • Trypanosoma brucei brucei / genetics
  • Trypanosoma brucei brucei / metabolism*

Substances

  • Alkylating Agents
  • Histones
  • Nuclear Proteins
  • Protozoan Proteins
  • Sirtuins
  • Histone Deacetylases