Mechanism And Function For The Centromeric Localization Of DNA Topoisomerase ??

Chromosome segregation in mitosis requires the removal of catenation between sister chromatids.Timely decatenation of sister DNAs at mitotic centromeres by topoisomerase II?(TOP2A)is crucial to maintain genomic stability.The chromatin factors that recruit TOP2 A to centromeres during mitosis remain unknown.Here,we show that histone H2 A Thr-120 phosphorylation(H2Ap T120),a modification generated by the mitotic kinase Bub1,is necessary and sufficient for the centromeric localization of TOP2 A.Phosphorylation at residue-120 enhances histone H2 A binding to TOP2 A in vitro.The C-gate and the extreme C-terminal region are important for H2 Ap T120-dependent localization of TOP2 A at centromeres.Preventing H2 Ap T120-mediated accumulation of TOP2 A at mitotic centromeres interferes with sister chromatid disjunction,as evidenced by increased frequency of anaphase ultra-fine bridges(UFBs)that contain catenated DNA.Tethering TOP2 A to centromeres bypasses the requirement for H2 Ap T120 in suppressing anaphase UFBs.These results demonstrate that H2 Ap T120 acts as a landmark that recruits TOP2 A to mitotic centromeres to decatenate sister DNAs.Our study reveals a fundamental role for histone phosphorylation in resolving centromere DNA entanglements and safeguarding genomic stability during mitosis.