Abstract
Chromosome duplication and transmission into daughter cells requires the precisely orchestrated binding and release of cohesin. We found that the Drosophila histone chaperone NAP1 is required for cohesin release and sister chromatid resolution during mitosis. Genome-wide surveys revealed that NAP1 and cohesin co-localize at multiple genomic loci. Proteomic and biochemical analysis established that NAP1 associates with the full cohesin complex, but it also forms a separate complex with the cohesin subunit stromalin (SA). NAP1 binding to cohesin is cell-cycle regulated and increases during G2/M phase. This causes the dissociation of protein phosphatase 2A (PP2A) from cohesin, increased phosphorylation of SA and cohesin removal in early mitosis. PP2A depletion led to a loss of centromeric cohesion. The distinct mitotic phenotypes caused by the loss of either PP2A or NAP1, were both rescued by their concomitant depletion. We conclude that the balanced antagonism between NAP1 and PP2A controls cohesin dissociation during mitosis.
Highlights
Histone chaperones perform crucial functions during the duplication of eukaryotic genomes [1,2]
We describe an unexpected function for the canonical histone chaperone NAP1 in sister chromatid resolution
Cohesin removal from the arms is initiated by mitotic kinases in early mitosis, but can be counteracted by protein phosphatase 2A (PP2A)
Summary
Histone chaperones perform crucial functions during the duplication of eukaryotic genomes [1,2]. In addition to replication-coupled chromatin assembly, histone chaperones function in gene-specific transcription control, DNA repair and direct specific histone modifications [10,11,12,13,14,15]. Histone chaperones achieve these diverse functions through cooperation with other factors, such as histone modifying enzymes and ATP-dependent chromatin remodelers [15,16,17,18,19,20]. ASF1 and NAP1 cooperates with histone modifying factors to differentially modulate local chromatin during NOTCH signaling [15,21]. NAP1 recruits RLAF to the (E)Spl NOTCH-regulated genes to generate a repressive chromatin structure and mediate transcriptional silencing [15]
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