TY - JOUR
T1 - Structural basis for Mis18 complex assembly and its implications for centromere maintenance
AU - Thamkachy, Reshma
AU - Medina-Pritchard, Bethan
AU - Park, Sang Ho
AU - Chiodi, Carla G.
AU - Zou, Juan
AU - de la Torre-Barranco, Maria
AU - Shimanaka, Kazuma
AU - Abad, Maria Alba
AU - Gallego Páramo, Cristina
AU - Feederle, Regina
AU - Ruksenaite, Emilija
AU - Heun, Patrick
AU - Davies, Owen R.
AU - Rappsilber, Juri
AU - Schneidman-Duhovny, Dina
AU - Cho, Uhn Soo
AU - Jeyaprakash, A. Arockia
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/8/9
Y1 - 2024/8/9
N2 - The centromere, defined by the enrichment of CENP-A (a Histone H3 variant) containing nucleosomes, is a specialised chromosomal locus that acts as a microtubule attachment site. To preserve centromere identity, CENP-A levels must be maintained through active CENP-A loading during the cell cycle. A central player mediating this process is the Mis18 complex (Mis18α, Mis18β and Mis18BP1), which recruits the CENP-A-specific chaperone HJURP to centromeres for CENP-A deposition. Here, using a multi-pronged approach, we characterise the structure of the Mis18 complex and show that multiple hetero- and homo-oligomeric interfaces facilitate the hetero-octameric Mis18 complex assembly composed of 4 Mis18α, 2 Mis18β and 2 Mis18BP1. Evaluation of structure-guided/separation-of-function mutants reveals structural determinants essential for cell cycle controlled Mis18 complex assembly and centromere maintenance. Our results provide new mechanistic insights on centromere maintenance, highlighting that while Mis18α can associate with centromeres and deposit CENP-A independently of Mis18β, the latter is indispensable for the optimal level of CENP-A loading required for preserving the centromere identity.
AB - The centromere, defined by the enrichment of CENP-A (a Histone H3 variant) containing nucleosomes, is a specialised chromosomal locus that acts as a microtubule attachment site. To preserve centromere identity, CENP-A levels must be maintained through active CENP-A loading during the cell cycle. A central player mediating this process is the Mis18 complex (Mis18α, Mis18β and Mis18BP1), which recruits the CENP-A-specific chaperone HJURP to centromeres for CENP-A deposition. Here, using a multi-pronged approach, we characterise the structure of the Mis18 complex and show that multiple hetero- and homo-oligomeric interfaces facilitate the hetero-octameric Mis18 complex assembly composed of 4 Mis18α, 2 Mis18β and 2 Mis18BP1. Evaluation of structure-guided/separation-of-function mutants reveals structural determinants essential for cell cycle controlled Mis18 complex assembly and centromere maintenance. Our results provide new mechanistic insights on centromere maintenance, highlighting that while Mis18α can associate with centromeres and deposit CENP-A independently of Mis18β, the latter is indispensable for the optimal level of CENP-A loading required for preserving the centromere identity.
KW - CENP-A
KW - Centromere
KW - Centromere Inheritance
KW - Integrative Structural Analysis
KW - Mis18 Complex
UR - http://www.scopus.com/inward/record.url?scp=85197315486&partnerID=8YFLogxK
U2 - 10.1038/s44319-024-00183-w
DO - 10.1038/s44319-024-00183-w
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C2 - 38951710
AN - SCOPUS:85197315486
SN - 1469-221X
VL - 25
SP - 3348
EP - 3372
JO - EMBO Reports
JF - EMBO Reports
IS - 8
ER -