A GTPase switch maintains CENP-A at centromeric chromatin

Prendergast, Lisa; Sullivan, Kevin F.

doi:10.1038/ncb1210-1128

Cited by 7 publications

(5 citation statements)

References 15 publications

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“…Recently, McKinley et al have shown that faithful CENP-A deposition requires integrated signals from Plk1 and cyclin-dependent kinase (CDK), with Plk1 promoting the localization of the Mis18 complex, and CDK inhibiting Mis18 complex assembly (McKinley and Cheeseman, 2014). In addition, the remodeling and spacing factor (RSF) complex actively supports the assembly of CENP-A chromatin (Perpelescu et al, 2009), and the CENP-A licensing factor M18BP1/KNL2 and the small GTPases-activating protein MgcRacGAP cooperate to promote the stability of newly loaded CENP-A at centromeres (Lagana et al, 2010; Prendergast and Sullivan, 2010). …”

Section: Introductionmentioning

confidence: 99%

CENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the Centromere

et al. 2015

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SUMMARY CENP-A is a centromere-specific histone H3 variant that epigenetically determines centromere identity to ensure kinetochore assembly and proper chromo-some segregation, but the precise mechanism of its specific localization within centromeric heterochromatin remains obscure. We have discovered that CUL4A-RBX1-COPS8 E3 ligase activity is required for CENP-A ubiquitylation on lysine 124 (K124) and CENP-A centromere localization. A mutation of CENP-A, K124R, reduces interaction with HJURP (a CENP-A-specific histone chaperone) and abrogates localization of CENP-A to the centromere. Addition of monoubiquitin is sufficient to restore CENP-A K124R to centromeres and the interaction with HJURP, indicating that “signaling” ubiquitylation is required for CENP-A loading at centromeres. The CUL4A-RBX1 complex is required for loading newly synthesized CENP-A and maintaining preassembled CENP-A at centromeres. Thus, CENP-A K124R ubiquitylation, mediated by the CUL4A-RBX1-COPS8 complex, is essential for CENP-A deposition at the centromere.

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Section: Introductionmentioning

confidence: 99%

CENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the Centromere

et al. 2015

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“…, 2007 ; Lagana et al. , 2010 ), a phenomenon referred to as CENP-A maturation ( Prendergast and Sullivan, 2010 ). Furthermore, analysis of longer-term maintenance in quiescent cells found a low degree of turnover of CENP-A nucleosomes by around 2–10% per day, indicating that CENP-A does turn over, albeit at a slow rate ( Swartz et al.…”

Section: Resultsmentioning

confidence: 99%

p97/VCP drives turnover of SUMOylated centromeric CCAN proteins and CENP-A

Berg

East

Mitra

et al. 2023

MBoC

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The centromere is a unique chromatin domain that links sister chromatids and forms the attachment site for spindle microtubules in mitosis. Centromere inheritance is largely DNA sequence-independent but strongly reliant on a self-propagating chromatin domain featuring nucleosomes containing the H3 variant CENP-A. Unlike other histones, CENP-A is maintained with unusually high stability in chromatin. Previously, we have shown that mitotic maintenance of CENP-A and other CCAN proteins is controlled by a dynamic SUMO cycle and that the deSUMOylase SENP6 is necessary for stable maintenance of CENP-A at the centromere. Here, we discover that the removal of SENP6 leads to a rapid loss of the constitutive centromere-associated network (CCAN), followed by a delayed loss of centromeric CENP-A, indicating that the CCAN is the primary SUMO target. We found the ATP-dependent segregase p97/VCP removes centromeric CENP-A in a SUMO-dependent manner and physically interacts with the CCAN and CENP-A chromatin. Our data suggest a direct role of p97 in removing centromeric CENP-A via SUMOylated CCAN proteins thereby ensuring centromere homeostasis and potentially preventing ectopic CENP-A accumulation.

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“…Faithful CENP-A deposition requires integrated signals from Plk1 and cyclindependent kinase (CDK), with Plk1 promoting the localization of the Mis18 complex, and CDK inhibiting Mis18 complex assembly [134]. Moreover, the remodeling and spacing factor complex is required for the assembly of CENP-A chromatin [135], and the CENP-A licensing factor M18BP1/KNL2 and the small GTPases-activating protein MgcRacGAP cooperate to maintain the stability of newly loaded CENP-A at centromeres [136,137].…”

Section: E3 Ligase For Human Cenp-a Its Function 41 Overview Of Human...mentioning

confidence: 99%

E3 Ligase for CENP-A (Part 2)

Niikura¹,

Kitagawa²

2022

Hydrolases

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Centromeric CENP-A, a variant of histone H3, plays a central role in proper chromosome segregation and its function is highly conserved among different species. In most species with regional centromeres, an active centromere relies not on defined DNA sequences, but on the presence of CENP-A proteins in centromeric nucleosomes. CENP-A is proposed to be the non-DNA indicator (epigenetic mark) that defines proper centromere assembly and function. Recently, many post-translational modifications (PTMs) of CENP-A and their functions have been reported. They revealed the importance of the functions of CENP-A PTMs in CENP-A deposition at centromeres, proteolysis/protein stability, and recruitment of other centromere-kinetochore proteins. Ubiquitylation and sumoylation by E3 ligases regulate multiple functions, including proteolysis and signaling, and play important roles in the cell cycle and mitotic control. Recently, the function of E3 ligase that ubiquitylates/sumoylates and controls CENP-A protein has emerged as an important regulatory paradigm in different species. Many have reported the importance of CENP-A ubiquitylation and sumoylation in CENP-A deposition at centromeres and for protein stability, which is regulated by specific E3 ligases. Therefore, here we summarize what is known about the E3 ligases for CENP-A ubiquitylation and sumoylation and their biological functions and significance in different species.

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A GTPase switch maintains CENP-A at centromeric chromatin

Cited by 7 publications

References 15 publications

CENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the Centromere

CENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the Centromere

p97/VCP drives turnover of SUMOylated centromeric CCAN proteins and CENP-A

E3 Ligase for CENP-A (Part 2)

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