Centromeric chromatin integrity is compromised by loss of Cdk5rap2, a transcriptional activator of CENP-A - 16/04/21
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Abstract |
Centromeres are chromosomal loci where kinetochores assemble to ensure faithful chromosome segregation during mitosis. CENP-A defines the loci by serving as an epigenetic marker that recruits other centromere components for a functional structure. However, the mechanism that controls CENP-A regulation of centromeric chromatin integrity remains to be explored. Separate studies have shown that loss of CENP-A or the Cdk5 regulatory subunit associated protein 2 (Cdk5rap2), a key player in mitotic progression, triggers the occurrence of lagging chromosomes. This prompted us to investigate a potential link between CENP-A and Cdk5rap2 in the maintenance of centromeric chromatin integrity. Here, we demonstrate that loss of Cdk5rap2 causes reduced CENP-A expression while exogenous Cdk5rap2 expression in cells depleted of endogenous Cdk5rap2 restores CENP-A expression. Indeed, we show that Cdk5rap2 is a nuclear protein that acts as a positive transcriptional regulator of CENP-A. Cdk5rap2 interacts with the CENP-A promoter and upregulates CENP-A transcription. Accordingly, loss of Cdk5rap2 causes reduced level of centromeric CENP-A. Exogenous CENP-A expression partially inhibits the occurrence of lagging chromosomes in Cdk5rap2 knockdown cells, indicating that lagging chromosomes induced by loss of Cdk5rap2 is due, in part, to loss of CENP-A. Aside from manifesting lagging chromosomes, cells depleted of Cdk5rap2, and thus CENP-A, show increased micronuclei and chromatin bridge formation. Altogether, our findings indicate that Cdk5rap2 serves to maintain centromeric chromatin integrity partly through CENP-A.
El texto completo de este artículo está disponible en PDF.Graphical Abstract |
Highlights |
• | Cdk5rap2 acts as a positive transcriptional regulator of CENP-A. |
• | Lagging chromosomes induced by loss of Cdk5rap2 is due to loss of CENP-A. |
• | Cdk5rap2 serves to maintain centromeric chromatin integrity through CENP-A. |
A list of abbreviations : Cdk5rap2, CENP-A, PCM, SMC, CM2, EMEM, FBS, DMEM
Keywords : Cell cycle, Cdk5rap2, CENP-A
Esquema
Vol 138
Artículo 111463- juin 2021 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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