A tale of two serines: the effects of histone H2A mutations S122A and S129A on chromosome nondisjunction in Saccharomyces cerevisiae.

Near the C-terminus of histone H2A in the yeast Saccharomyces cerevisiae, there are 2 serines (S122 and S129) that are targets of phosphorylation. The phosphorylation of serine 129 in response to DNA damage is dependent on the Tel1 and Mec1 kinases. In Schizosaccharomyces pombe and S. cerevisiae, the phosphorylation of serine 122 is dependent on the Bub1 kinase, and S. pombe strains with an alanine mutation of this serine have elevated levels of lagging chromosomes in mitosis. Strains that lack both Tel1 and Mec1 in S. cerevisiae have very elevated rates of nondisjunction. To clarify the functional importance of phosphorylation of serines 122 and 129 in H2A, we measured chromosome loss rates in single-mutant strains and double-mutant combinations. We also examined the interaction of mutations of BUB1, TEL1, and MEC1 in combination with mutations of serines 122 and 129 in H2A. We conclude that the phosphorylation state of S129 has no effect on chromosome disjunction whereas mutations that inactivate Bub1 or a S122A mutation in the histone H2A greatly elevate the rate of chromosome nondisjunction. Based on this analysis, we suggest that Bub1 exerts its primary effect on chromosome disjunction by phosphorylating S122 of histone H2A. However, Tel1, Mec1, and Bub1 are also functionally redundant in a second pathway affecting chromosome disjunction that is at least partially independent of phosphorylation of S122 of H2A.