Phosphorylation of CENP-R by Aurora B regulates kinetochore–microtubule attachment for accurate chromosome segregation

Abstract

Error-free mitosis depends on accurate chromosome attachment to spindle microtubules via a fine structure called the centromere that is epigenetically specified by the enrichment of CENP-A nucleosomes. Centromere maintenance during mitosis requires CENP-A-mediated deposition of constitutive centromere-associated network (CCAN) that establishes the inner kinetochore and connects centromeric chromatin to spindle microtubules during mitosis. Although previously proposed to be an adaptor of retinoic acid receptor, here, we show that CENP-R synergizes with CENP-OPQU to regulate kinetochore–microtubule attachment stability and ensure accurate chromosome segregation in mitosis. We found that a phospho-mimicking mutation of CENP-R weakened its localization to the kinetochore, suggesting that phosphorylation may regulate its localization. Perturbation of CENP-R phosphorylation is shown to prevent proper kinetochore–microtubule attachment at metaphase. Mechanistically, CENP-R phosphorylation disrupts its binding with CENP-U. Thus, we speculate that Aurora B-mediated CENP-R phosphorylation promotes the correction of improper kinetochore–microtubule attachment in mitosis. As CENP-R is absent from yeast, we reasoned that metazoan evolved an elaborate chromosome stability control machinery to ensure faithful chromosome segregation in mitosis.

A non-canonical role of the inner kinetochore in regulating sister-chromatid cohesion at centromeres

“…Using chicken DT-40 cells, it was previously shown that CENP-U depletion caused a defect in the recovery of mitosis progression from spindle damage (Hori et al, 2008 ). It is unknown whether this phenotype is due to cohesion defects, or to the impaired function of the CENP-O/P/Q/U/R subunits in modulating kinetochore-microtubule attachment (Amaro et al, 2010 ; Bancroft et al, 2015 ; Hua et al, 2011 ; Pesenti et al, 2018 ; Sedzro et al, 2022 ). If the former is the case, it will be interesting to examine whether the CENP-O, P, Q, or R subunit of the vertebrate CENP-OPQUR complex contains the F/Y-x-F motif that can bind to the Scc1-SA2 sub-complex.…”

CENPA functions as a transcriptional regulator to promote hepatocellular carcinoma progression via cooperating with YY1

“…Protein post-transcriptional modification (PTM) influence fundamental properties and cellular biological process, including gene transcription, protein attachment, metabolic reprogramming and so on [21,22]. Several types of PTM with essential functions have been identified on CENPA, including phosphorylation, ubiquitylation, methylation, and acetylation [23][24][25][26].…”