title: Sirtuin inhibition increases the rate of non-homologous end-joining of DNA double strand breaks.
abstract: Sirtuins (type III histone deacetylases) are an important member of a group of enzymes that modify chromatin conformation. We investigated the role of sirtuin inhibitor, GPI 19015, in double strand break (DSB) repair in CHO-K1 wt and xrs-6 mutant cells. The latter is defective in DNA-dependent protein kinase (DNA-PK)-mediated non-homologous end-joining (D-NHEJ). DSB were estimated by the neutral comet assay and histone gammaH2AX foci formation. We observed a weaker effect of GPI 19015 treatment on the repair kinetics in CHO wt cells than in xrs6. In the latter cells the increase in DNA repair rate was most pronounced in G1 phase and practically absent in S and G2 cell cycle phases. The decrease in the number of histone gammaH2AX foci was faster in xrs6 than in CHO-K1 cells. The altered repair rate did not affect survival of X-irradiated cells. Since in G1 xrs6 cells DNA-PK-dependent non-homologous end-joining, D-NHEJ, does not operate, these results indicate that inhibition of sirtuins modulates DNA-PK-independent (backup) non-homologous end-joining, B-NHEJ, to a greater extent than the other DSB repair system, D-NHEJ.
authors.affiliation: Department of Radiobiology and Health Protection, Institute of Nuclear Chemistry and Technology, Warszawa, Poland. marylaw@ichtj.waw.pl
authors.forename: Maria
authors.initials: M
authors.lastname: Wojewódzka
authors.forename: Marcin
authors.initials: M
authors.lastname: Kruszewski
authors.forename: Iwona
authors.initials: I
authors.lastname: Buraczewska
authors.forename: Weizheng
authors.initials: W
authors.lastname: Xu
authors.forename: Edmond
authors.initials: E
authors.lastname: Massuda
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Irena
authors.initials: I
authors.lastname: Szumiel
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004260:DNA Repair; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D007700:Kinetics; D009154:Mutation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D037761:Sirtuins / Q000037:antagonists & inhibitors*
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D037761:Sirtuins; D056464:Histone Deacetylase 2