Molecular Bases Of Mitotic Regulation Mechanisms And Centromere Epigenetical Inheritance

During cell division, chromosome segregation is orchestrated by the interaction of spindle microtubules with the centromere. Accurate attachment of spindle microtubules to kinetochore requires the chromosomal passenger of Aurora-B kinase complex with borealin, INCENP and survivin. However, the chromatin factors that recruit the CPC to centromeres have remained elusive. Here we show that borealin interacts with heterochromatin protein1α (HP1α) and this interaction is mediated by an evolutionarily conserved PxVxL motif in borealin and the chromatin shadow domain of HP1α. This borealin-HP1α binding recruits the CPC to the centromere and the resulting activation of its kinase subunit Aurora-B judged by phosphorylation of Ser7-CENP-A. Consistently, modulation of the binding motif PxVxL, leads to defects in CPC centromere targeting and aberrant Aurora-B activity. On the other hand, the localization of CPC in midzone is independent of Borealin-HP1αinteraction, demonstrating the spatial requirement of HP1α in CPC localization.to the centromere. These findings establish a previously unrecognized but direct link between HP1αand CPC plasticity in centromere and illustrate its critical role of borealin-HPla interaction in orchestrating an accurate cell division.Centromere is a chromatin region on which the kinetochore is assembled to mediate sister chromatid separation during cell division. In multi-cellular organisms centromere inheritance is mostly regulated by epigenetical mechanisms. Centromere protein A (CENP-A), a centromere specific variant of histone H3,is considered as the most important epigenetic marker for centromere specification. However, the molecular mechanism underlying centromere specific assembly of CENP-A is still unclear. Here we report that the Ser68of CENP-A plays an important role in accurate loading of CENP-A onto centromeric DNA, and this process is independent of its interaction with HJURP, a CENP-A specific Chaperone protein. Current efforts are directed to delineate the molecular machinery responsible for CENP-A assembly onto the centromeric chromatin, which will shed light onto a better understanding of centromere plasticity and chromosome stability during cell division.