Centromeric chromatin integrity is compromised by loss of Cdk5rap2, a transcriptional activator of CENP-A

Wang, Xidi; Rosales, Jesusa L.; Gao, Xu; Lee, Ki-Young

doi:10.1016/j.biopha.2021.111463

Cited by 6 publications

(5 citation statements)

References 37 publications

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“…Deletion of Cdk5rap2 results in a reduced expression level of CENP-A RNA. The study further showed that transcriptional regulation of CENP-A by Cdk5rap2 partially contributes to the chromosome segregation defects observed in the Cdk5rap2 knockdown cells [151].…”

Section: Cell-cycle Regulation Of Cenp-a Transcription As a Key Control Mechanism For Cenp-a Levelmentioning

confidence: 99%

“…Reduction of CENP-A RNAs causes lagging chromosomes [139,150]. A recent study found that the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (Cdk5rap2) functions as a transcriptional activator of CENP-A in human cells [151]. Cdk5rap2 binds the CENP-A promoter and upregulates CENP-A transcription.…”

Section: Cell-cycle Regulation Of Cenp-a Transcription As a Key Contr...mentioning

confidence: 99%

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Recent insights into mechanisms preventing ectopic centromere formation

et al. 2021

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The centromere is a specialized chromosomal structure essential for chromosome segregation. Centromere dysfunction leads to chromosome segregation errors and genome instability. In most eukaryotes, centromere identity is specified epigenetically by CENP-A, a centromere-specific histone H3 variant. CENP-A replaces histone H3 in centromeres, and nucleates the assembly of the kinetochore complex. Mislocalization of CENP-A to non-centromeric regions causes ectopic assembly of CENP-A chromatin, which has a devastating impact on chromosome segregation and has been linked to a variety of human cancers. How non-centromeric regions are protected from CENP-A misincorporation in normal cells is largely unexplored. Here, we review the most recent advances on the mechanisms underlying the prevention of ectopic centromere formation, and discuss the implications in human disease.

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Section: Cell-cycle Regulation Of Cenp-a Transcription As a Key Control Mechanism For Cenp-a Levelmentioning

confidence: 99%

Section: Cell-cycle Regulation Of Cenp-a Transcription As a Key Contr...mentioning

confidence: 99%

Recent insights into mechanisms preventing ectopic centromere formation

et al. 2021

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“…Media was then replaced with EMEM containing 10% FBS 24 h post infection and cells were incubated until the indicated time. We have previously tested and established the specificity of CDK5RAP2 siRNA #1 and #2 effects in BJ cells [ 54 ].…”

Section: Methodsmentioning

confidence: 99%

CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway

Wang

Sipila

et al. 2021

Cell Death Dis

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Developmental disorders characterized by small body size have been linked to CDK5RAP2 loss-of-function mutations, but the mechanisms underlying which remain obscure. Here, we demonstrate that knocking down CDK5RAP2 in human fibroblasts triggers premature cell senescence that is recapitulated in Cdk5rap2an/an mouse embryonic fibroblasts and embryos, which exhibit reduced body weight and size, and increased senescence-associated (SA)-β-gal staining compared to Cdk5rap2+/+ and Cdk5rap2+/an embryos. Interestingly, CDK5RAP2-knockdown human fibroblasts show increased p53 Ser15 phosphorylation that does not correlate with activation of p53 kinases, but rather correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses the senescent phenotype in CDK5RAP2-knockdown cells, indicating that senescence in these cells is linked to WIP1 downregulation. CDK5RAP2 interacts with GSK3β, causing increased inhibitory GSK3β Ser9 phosphorylation and inhibiting the activity of GSK3β, which phosphorylates β-catenin, tagging β-catenin for degradation. Thus, loss of CDK5RAP2 decreases GSK3β Ser9 phosphorylation and increases GSK3β activity, reducing nuclear β-catenin, which affects the expression of NF-κB target genes such as WIP1. Consequently, loss of CDK5RAP2 or β-catenin causes WIP1 downregulation. Inhibition of GSK3β activity restores β-catenin and WIP1 levels in CDK5RAP2-knockdown cells, reducing p53 Ser15 phosphorylation and preventing senescence in these cells. Conversely, inhibition of WIP1 activity increases p53 Ser15 phosphorylation and senescence in CDK5RAP2-depleted cells lacking GSK3β activity. These findings indicate that loss of CDK5RAP2 promotes premature cell senescence through GSK3β/β-catenin downregulation of WIP1. Premature cell senescence may contribute to reduced body size associated with CDK5RAP2 loss-of-function.

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“…The periodic transcription of CENP-A Cnp1 is lost in MBF mutants, resulting in the higher level of CENP-A Cnp1 and chromosome segregation defects [ 37 ]. A recent study has also shown that the Cdk5 regulatory subunit-associated protein 2 (Cdk5rap2) acts as a positive transcriptional regulator of CENP-A in human cells [ 38 ]. Regional centromeres are typically buried in a large pericentric heterochromatin, a condensed and transcriptionally inert chromatin domain lacking CENP-A [ 39 , 40 ].…”

Section: Centromeresmentioning

confidence: 99%

Cell cycle control of kinetochore assembly

Dong

2022

Nucleus

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The kinetochore is a large proteinaceous structure assembled on the centromeres of chromosomes. The complex machinery links chromosomes to the mitotic spindle and is essential for accurate chromosome segregation during cell division. The kinetochore is composed of two submodules: the inner and outer kinetochore. The inner kinetochore is assembled on centromeric chromatin and persists with centromeres throughout the cell cycle. The outer kinetochore attaches microtubules to the inner kinetochore, and assembles only during mitosis. The review focuses on recent advances in our understanding of the mechanisms governing the proper assembly of the outer kinetochore during mitosis and highlights open questions for future investigation.

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Centromeric chromatin integrity is compromised by loss of Cdk5rap2, a transcriptional activator of CENP-A

Cited by 6 publications

References 37 publications

Recent insights into mechanisms preventing ectopic centromere formation

Recent insights into mechanisms preventing ectopic centromere formation

CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway

Cell cycle control of kinetochore assembly

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