title: Histone dosage regulates DNA damage sensitivity in a checkpoint-independent manner by the homologous recombination pathway.
abstract: In eukaryotes, multiple genes encode histone proteins that package genomic deoxyribonucleic acid (DNA) and regulate its accessibility. Because of their positive charge, 'free' (non-chromatin associated) histones can bind non-specifically to the negatively charged DNA and affect its metabolism, including DNA repair. We have investigated the effect of altering histone dosage on DNA repair in budding yeast. An increase in histone gene dosage resulted in enhanced DNA damage sensitivity, whereas deletion of a H3-H4 gene pair resulted in reduced levels of free H3 and H4 concomitant with resistance to DNA damaging agents, even in mutants defective in the DNA damage checkpoint. Studies involving the repair of a HO endonuclease-mediated DNA double-strand break (DSB) at the MAT locus show enhanced repair efficiency by the homologous recombination (HR) pathway on a reduction in histone dosage. Cells with reduced histone dosage experience greater histone loss around a DSB, whereas the recruitment of HR factors is concomitantly enhanced. Further, free histones compete with the HR machinery for binding to DNA and associate with certain HR factors, potentially interfering with HR-mediated repair. Our findings may have important implications for DNA repair, genomic stability, carcinogenesis and aging in human cells that have dozens of histone genes.
authors: Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306-4300, USA.
authors: Dun
authors: D
authors: Liang
authors: Sarah Lyn
authors: SL
authors: Burkhart
authors: Rakesh Kumar
authors: RK
authors: Singh
authors: Marie-Helene Miquel
authors: MH
authors: Kabbaj
authors: Akash
authors: A
authors: Gunjan
mesh_terms: D002843:Chromatin / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D018628:Gene Dosage; D015870:Gene Expression; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic; D059767:Recombinational DNA Repair; D004718:Saccharomycetales / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones