Journal
MOLECULAR CELL
Volume 65, Issue 2, Pages 231-246Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.11.021
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Funding
- Fundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BD/51878/2012, SFRH/BD/74284/2010, BIA-BCM/100557/2008]
- NIH/National Institute of General Medical Sciences (NIGMS) [R01-GM082989, T32-GM008275]
- NIH/NCI [F30-CA186430]
- NIH [GM 037537, GM 110174]
- EMBO installation grant [1818]
- ERC-consolidator grant [ERC-2013-CoG-615638]
- Investigador FCT'' position
- Fundação para a Ciência e a Tecnologia [SFRH/BD/51878/2012, SFRH/BD/74284/2010, PTDC/BIA-BCM/100557/2008] Funding Source: FCT
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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.
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