A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae.
Rad53 and Mec1 are protein kinases required for DNA replication and recovery from DNA damage in Saccharomyces cerevisiae. Here, we show that rad53, but not mec1 mutants, are extremely sensitive to histone overexpression, as Rad53 is required for degradation of excess histones. Consequently, excess histones accumulate in rad53 mutants, resulting in slow growth, DNA damage sensitivity, and chromosome loss phenotypes that are significantly suppressed by a reduction in histone gene dosage. Rad53 monitors excess histones by associating with them in a dynamic complex that is modulated by its kinase activity. Our results argue that Rad53 contributes to genome stability independently of Mec1 by preventing the damaging effects of excess histones both during normal cell cycle progression and in response to DNA damage.
Gunjan
Akash
A
Cancer Research UK, London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire EN6 3LD, United Kingdom.
Verreault
Alain
A
D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000235:genetics*; D018628:Gene Dosage; D015966:Gene Expression Regulation, Fungal / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D046911:Macromolecular Substances; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D015854:Up-Regulation / Q000235:genetics
D018797:Cell Cycle Proteins; D006657:Histones; D046911:Macromolecular Substances; D029701:Saccharomyces cerevisiae Proteins; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae