Dynamic Phosphorylation of CENP-A at Ser68 Orchestrates Its Cell-Cycle-Dependent Deposition at Centromeres

Yu, Zhouliang; Zhou, Xiang; Wang, Wenjing; Deng, Wenqiang; Fang, Junshun; Hu, Hao; Wang, Zi-Chen; Li, Shangze; Cui, Lei; Shen, Jing; Zhai, Linhui; Shan, Peng; Wong, Jiemin; Dong, Shuang; Yuan, Zengqiang; Ou, Guangshuo; Zhang, Xiaodong; Xu, Ping; Lou, Jizhong; Yang, Na; Chen, Ping; Xu, Rui-Ming; Li, Guohong

doi:10.1016/j.devcel.2014.11.030

Cited by 93 publications

(120 citation statements)

References 47 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…Several studies suggested that mitotic cyclins and CDK1/2 kinase activity are inhibitory for ectopic CENP-A loading by mediating phosphorylation of M18BP1, HJURP and the Ser68 residue of CENP-A itself (18–20). Cyclin E1 forms a functional kinase complex with CDK2 at the G1/S boundary to regulate cell cycle progression into S phase (36).…”

Section: Resultsmentioning

confidence: 99%

“…4G). A recent study suggested that Cyclin B1/CDK1 phosphorylates CENP-A at Ser68 (20). Depletion of Cyclin E1 or CDK2 by shRNAs had no impact on CENP-A Ser68 phosphorylation levels by western blotting (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Chinese hamster ovary DG44 cells (Named as A03_1) containing LacO arrays at a single non-centromeric locus (Fig. S5A) (20) were co-transfected with mCherry-LacI-fused HJURP and EGFP-tagged WT, S18D or S18A mutant CENP-A, respectively. For EGFP-tagged WT or S18A CENP-A, we observed EGFP signals predominately at the LacO arrays as indicated by colocalization with mCherry-LacI-HJURP.…”

Section: Resultsmentioning

confidence: 99%

“…For example, phosphorylation of M18BP1 and HJURP by CDK1/2 prevents nucleosome assembly in S and G2 phases, and inhibition of CDK1/2 activity is required for CENP-A loading (18,19). Moreover, phosphorylation of CENP-A at Ser68 mediated by Cyclin B/CDK1 might also be important for proper CENP-A localization despite some debates (20–22). Finally, phosphorylation of CENP-A N-terminus at Ser16 and Ser18 residues has been implicated in chromosome segregation (23).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

et al. 2017

Self Cite

View full text Add to dashboard Cite

The centromere regulates proper chromosome segregation and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here we define the consequences of phosphorylation by Cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to chromosomal instability (CIN). This event on CENP-A reduced its centromeric localization, increased CIN and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that Cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…The structure of centromeric chromatin undergoes cell cycle-dependent transitions Recently, a number of studies demonstrated that the assembly of CENP-A is temporally regulated by phosphorylation/dephosphorylation of CENP-A at Ser68 (Yu et al 2015), chaperone HJURP , and the "priming" factor Mis18 complex (McKinley and Cheeseman 2014). The tight regulation results in a change of CENP-A in a strictly cell cycle-dependent manner and ensures proper centromere function during mitosis after temporal recruitment of specific kinetochore proteins.…”

Section: Cenp-a Chromatin Displays a Distinct Higher-order Organizationmentioning

confidence: 99%

Structural transitions of centromeric chromatin regulate the cell cycle-dependent recruitment of CENP-N

et al. 2015

Self Cite

View full text Add to dashboard Cite

Specific recognition of centromere-specific histone variant CENP-A-containing chromatin by CENP-N is an essential process in the assembly of the kinetochore complex at centromeres prior to mammalian cell division. However, the mechanisms of CENP-N recruitment to centromeres/kinetochores remain unknown. Here, we show that a CENP-A-specific RG loop (Arg80/Gly81) plays an essential and dual regulatory role in this process. The RG loop assists the formation of a compact "ladder-like" structure of CENP-A chromatin, concealing the loop and thus impairing its role in recruiting CENP-N. Upon G1/S-phase transition, however, centromeric chromatin switches from the compact to an open state, enabling the now exposed RG loop to recruit CENP-N prior to cell division. Our results provide the first insights into the mechanisms by which the recruitment of CENP-N is regulated by the structural transitions between compaction and relaxation of centromeric chromatin during the cell cycle.

show abstract

Orchestrating the Specific Assembly of Centromeric Nucleosomes

Zasadzińska

Foltz

2017

Progress in Molecular and Subcellular Biology

View full text Add to dashboard Cite

Centromeres are chromosomal loci that are defined epigenetically in most eukaryotes by incorporation of a centromere-specific nucleosome in which the canonical histone H3 variant is replaced by Centromere Protein A (CENP-A). Therefore, the assembly and propagation of centromeric nucleosomes are critical for maintaining centromere identify and ensuring genomic stability. Centromeres direct chromosome segregation (during mitosis and meiosis) by recruiting the constitutive centromere-associated network of proteins throughout the cell cycle that in turn recruits the kinetochore during mitosis. Assembly of centromere-specific nucleosomes in humans requires the dedicated CENP-A chaperone HJURP, and the Mis18 complex to couple the deposition of new CENP-A to the site of the pre-existing centromere, which is essential for maintaining centromere identity. Human CENP-A deposition occurs specifically in early G1, into pre-existing chromatin, and several additional chromatin-associated complexes regulate CENP-A nucleosome deposition and stability. Here we review the current knowledge on how new CENP-A nucleosomes are assembled selectively at the existing centromere in different species and how this process is controlled to ensure stable epigenetic inheritance of the centromere.

show abstract

Dynamic Phosphorylation of CENP-A at Ser68 Orchestrates Its Cell-Cycle-Dependent Deposition at Centromeres

Cited by 93 publications

References 47 publications

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A

Structural transitions of centromeric chromatin regulate the cell cycle-dependent recruitment of CENP-N

Orchestrating the Specific Assembly of Centromeric Nucleosomes

Contact Info

Product

Resources

About