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1.
Mol Cell ; 83(7): 1075-1092.e9, 2023 04 06.
Article in English | MEDLINE | ID: mdl-36868228

ABSTRACT

A multitude of histone chaperones are required to support histones from their biosynthesis until DNA deposition. They cooperate through the formation of histone co-chaperone complexes, but the crosstalk between nucleosome assembly pathways remains enigmatic. Using exploratory interactomics, we define the interplay between human histone H3-H4 chaperones in the histone chaperone network. We identify previously uncharacterized histone-dependent complexes and predict the structure of the ASF1 and SPT2 co-chaperone complex, expanding the role of ASF1 in histone dynamics. We show that DAXX provides a unique functionality to the histone chaperone network, recruiting histone methyltransferases to promote H3K9me3 catalysis on new histone H3.3-H4 prior to deposition onto DNA. Hereby, DAXX provides a molecular mechanism for de novo H3K9me3 deposition and heterochromatin assembly. Collectively, our findings provide a framework for understanding how cells orchestrate histone supply and employ targeted deposition of modified histones to underpin specialized chromatin states.


Subject(s)
Histone Chaperones , Histones , Humans , Histones/metabolism , Histone Chaperones/genetics , Histone Chaperones/metabolism , Nucleosomes/genetics , Cell Cycle Proteins/metabolism , DNA , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Co-Repressor Proteins/genetics , Co-Repressor Proteins/metabolism
2.
EMBO Rep ; 22(7): e52295, 2021 07 05.
Article in English | MEDLINE | ID: mdl-33973335

ABSTRACT

The shugoshin proteins are universal protectors of centromeric cohesin during mitosis and meiosis. The binding of human hSgo1 to the PP2A-B56 phosphatase through a coiled-coil (CC) region mediates cohesion protection during mitosis. Here we undertook a structure function analysis of the PP2A-B56-hSgo1 complex, revealing unanticipated aspects of complex formation and function. We establish that a highly conserved pocket on the B56 regulatory subunit is required for hSgo1 binding and cohesion protection during mitosis in human somatic cells. Consistent with this, we show that hSgo1 blocks the binding of PP2A-B56 substrates containing a canonical B56 binding motif. We find that PP2A-B56 bound to hSgo1 dephosphorylates Cdk1 sites on hSgo1 itself to modulate cohesin interactions. Collectively our work provides important insight into cohesion protection during mitosis.


Subject(s)
Cell Cycle Proteins , Protein Phosphatase 2 , CDC2 Protein Kinase , Cell Cycle Proteins/genetics , Centromere , Humans , Meiosis , Mitosis , Protein Phosphatase 2/genetics
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