A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly

Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation. Simultaneous expression of mutant proteins lacking these residues results in complete uncoupling from the cell cycle. Consequently, CENP-A assembly is fully recapitulated under high Cdk activities, indistinguishable from G1 assembly. We find that Cdk-mediated inhibition is exerted by sequestering active factors away from the centromere. Finally, we show that displacement of M18BP1 from the centromere is critical for the assembly mechanism of CENP-A.

Descrição

The deposited article is a post-print version and has peer review. The deposited article version contains attached the supplementary materials within the pdf. This publication hasn't any creative commons license associated.

Palavras-chave

centromere histone variant CENP-A mitosis epigenetics chromatin cyclin dependent kinase cell cycle kinetochore

URI

http://hdl.handle.net/10400.7/804

Citação

Ana Stankovic, Lucie Y. Guo, João F. Mata, Dani L. Bodor, Xing-Jun Cao, Aaron O. Bailey, Jeffrey Shabanowitz, Donald F. Hunt, Benjamin A. Garcia, Ben E. Black, Lars E.T. Jansen, A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly, In Molecular Cell, Volume 65, Issue 2, 2017, Pages 231-246, ISSN 1097-2765, https://doi.org/10.1016/j.molcel.2016.11.021. (http://www.sciencedirect.com/science/article/pii/S1097276516307572)