Actively-transcribing RNA polymerase (RNAP)II is remained on centromeres to maintain centromeric cohesion during mitosis, although it is largely released from chromosome arms. This pool of RNAPII plays an important role in centromere functions. However, the mechanism of RNAPII retention on mitotic centromeres is poorly understood. We here demonstrate that Cyclin-dependent kinase (Cdk)11 is involved in RNAPII regulation on mitotic centromeres. Consistently, we show that Cdk11 knockdown induces centromeric cohesion defects and decreases Bub1 on kinetochores, but the centromeric cohesion defects are partially attributed to Bub1. Furthermore, Cdk11 knockdown and the expression of its kinase-dead version significantly reduce both RNAPII and elongating RNAPII (pSer2) levels on centromeres and decrease centromeric transcription. Importantly, the overexpression of centromeric α-satellite RNAs fully rescues Cdk11-knockdown defects. These results suggest that the maintenance of centromeric cohesion requires Cdk11-facilitated centromeric transcription. Mechanistically, Cdk11 localizes on centromeres where it binds and phosphorylates RNAPII to promote transcription. Remarkably, mitosis-specific degradation of G2/M Cdk11-p58 recapitulates Cdk11-knockdown defects. Altogether, our findings establish Cdk11 as an important regulator of centromeric transcription and as part of the mechanism for retaining RNAPII on centromeres during mitosis.
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http://dx.doi.org/10.1091/mbc.E23-08-0303 | DOI Listing |
Front Biosci (Landmark Ed)
January 2025
The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University Health Science Center, 410013 Changsha, Hunan, China.
Background: α thalassemia/mental retardation syndrome X-linked (ATRX) serves as a part of the sucrose nonfermenting 2 (SNF2) chromatin-remodeling complex. In interphase, ATRX localizes to pericentromeric heterochromatin, contributing to DNA double-strand break repair, DNA replication, and telomere maintenance. During mitosis, most ATRX proteins are removed from chromosomal arms, leaving a pool near the centromere region in mammalian cells, which is critical for accurate chromosome congression and sister chromatid cohesion protection.
View Article and Find Full Text PDFNat Commun
December 2024
Department of Meiosis, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
Aneuploidy in eggs is a leading cause of miscarriages or viable developmental syndromes. Aneuploidy rates differ between individual chromosomes. For instance, chromosome 21 frequently missegregates, resulting in Down Syndrome.
View Article and Find Full Text PDFDNA Repair (Amst)
December 2024
College of Chemistry, Fuzhou University, Fuzhou 350108, China. Electronic address:
Stromal antigen 1 and 2 (STAG1 and STAG2) are two mutually exclusive components of the cohesin complex that is crucial for centromeric and telomeric cohesion. Beyond its structural role, STAG2 also plays a pivotal role in homologous recombination (HR) repair and has emerged as a promising therapeutic target in cancer treatment. Here, we employed a fluorescence polarization (FP)-based high-throughput screening and identified KPT-6566 as a dual inhibitor of STAG1 and STAG2.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
November 2024
Laboratory of Cell Biophysics, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb 10000, Croatia.
Cancer cells often display errors in chromosome segregation, some of which result from improper chromosome alignment at the spindle midplane. Chromosome alignment is facilitated by different rates of microtubule poleward flux between sister kinetochore fibers. However, the role of the poleward flux in supporting mitotic fidelity remains unknown.
View Article and Find Full Text PDFNat Plants
September 2024
Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, NY, USA.
Retrotransposons have invaded eukaryotic centromeres in cycles of repeat expansion and purging, but the function of centromeric retrotransposons has remained unclear. In Arabidopsis, centromeric ATHILA retrotransposons give rise to epigenetically activated short interfering RNAs in mutants in DECREASE IN DNA METHYLATION1 (DDM1). Here we show that mutants that lose both DDM1 and RNA-dependent RNA polymerase have pleiotropic developmental defects and mis-segregate chromosome 5 during mitosis.
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