Molecular basis for Cdk1‐regulated timing of Mis18 complex assembly and CENP‐A deposition

Spiller, Frances; Medina‐Pritchard, Bethan; Abad, Maria Alba; Wear, Martin A.; Molina, Òscar; Jeyaprakash, A. Arockia

doi:10.15252/embr.201643564

Cited by 55 publications

(96 citation statements)

References 33 publications

(73 reference statements)

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“…The Mis18 complex binds HJURP directly and is required for the recruitment of HJURP and new CENP-A to the centromere in G1-phase [38,46–50] (Figure 3a). The human Mis18 complex forms an oligomeric structure that includes Mis18α and Mis18β paralogs, and Mis18BP1 [51 •• ,52 •• ]. CENP-C has been shown to participate in recruiting the Mis18 complex proteins to the existing centromere; although, it is unclear whether this interaction fully accounts for Mis18 recruitment [53–55].…”

Section: Cell Cycle Control Of Centromere Inheritancementioning

confidence: 99%

“…Mis18BP1 and HJURP are the major targets of CDK phosphorylation in the CENP-A deposition pathway [51 •• ,52 •• ,59,62,63 •• ] (Figure 3a,b). The expression of Mis18BP1 containing mutations within the CDK phosphorylation sites leads to CENP-A loading in G2; however, the level of CENP-A deposited is much lower than that observed in G1 [51 •• ,59,63 •• ].…”

Section: Cell Cycle Control Of Centromere Inheritancementioning

confidence: 99%

“…The expression of Mis18BP1 containing mutations within the CDK phosphorylation sites leads to CENP-A loading in G2; however, the level of CENP-A deposited is much lower than that observed in G1 [51 •• ,59,63 •• ]. Phosphorylation of sites within the Mis18α/β binding domain in the amino terminus of Mis18BP1, specifically Thr40 and Ser110, inhibit the binding of the Mis18α/β heterohexamer [51 •• ,52 •• ] (Figure 3b), providing a molecular basis of the inhibition of CENP-A deposition by CDK1 phosphorylation of Mis18BP1. Phosphorylation of Thr653 also inhibits recruitment of the Mis18 complex to centromeres, but lies outside of the Mis18α/β interaction domain [63 •• ], suggesting there is more to be learned about how phosphorylation by CDK1 inhibits this complex.…”

Section: Cell Cycle Control Of Centromere Inheritancementioning

confidence: 99%

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Posttranslational mechanisms controlling centromere function and assembly

Srivastava

Zasadzińska

Foltz

2018

Current Opinion in Cell Biology

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Accurate chromosome segregation is critical to ensure the faithful inheritance of the genome during cell division. Human chromosomes distinguish the location of the centromere from general chromatin by the selective assembly of CENP-A containing nucleosomes at the active centromere. The location of centromeres in most higher eukaryotes is determined epigenetically, independent of DNA sequence. CENP-A containing centromeric chromatin provides the foundation for assembly of the kinetochore that mediates chromosome attachment to the microtubule spindle and controls cell cycle progression in mitosis. Here we review recent work demonstrating the role of posttranslational modifications on centromere function and CENP-A inheritance via the direct modification of the CENP-A nucleosome and pre-nucleosomal complexes, the modification of the CENP-A deposition machinery and the modification of histones within existing centromeres.

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Section: Cell Cycle Control Of Centromere Inheritancementioning

confidence: 99%

Section: Cell Cycle Control Of Centromere Inheritancementioning

confidence: 99%

Section: Cell Cycle Control Of Centromere Inheritancementioning

confidence: 99%

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Posttranslational mechanisms controlling centromere function and assembly

Srivastava

Zasadzińska

Foltz

2018

Current Opinion in Cell Biology

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“…In contrast, CDK activity regulates multiple components of the deposition machinery to inhibit CENP-A deposition until mitosis is completed. Mis18BP1 is a substrate for CDK1 phosphorylation, and modification of the protein disrupts the association of the protein with the Mis18 α / β hexamer (Pan et al 2017; Silva et al 2012; Spiller et al 2017). CDK1 also phosphorylates HJURP to inhibit CENP-A deposition (Muller et al 2014; Stankovic et al 2017).…”

Section: Cenp-a Posttranslational Modifications and Deposition At Cenmentioning

confidence: 99%

Posttranslational modifications of CENP-A: marks of distinction

Srivastava

Foltz

2018

Chromosoma

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Centromeres are specialized chromosome domain that serve as the site for kinetochore assembly and microtubule attachment during cell division, to ensure proper segregation of chromosomes. In higher eukaryotes, the identity of active centromeres is marked by the presence of CENP-A (centromeric protein-A), a histone H3 variant. CENP-A forms a centromere-specific nucleosome that acts as a foundation for centromere assembly and function. The posttranslational modification (PTM) of histone proteins is a major mechanism regulating the function of chromatin. While a few CENP-A site-specific modifications are shared with histone H3, the majority are specific to CENP-A-containing nucleosomes, indicating that modification of these residues contribute to centromere-specific function. CENP-A undergoes posttranslational modifications including phosphorylation, acetylation, methylation, and ubiquitylation. Work from many laboratories have uncovered the importance of these CENP-A modifications in its deposition at centromeres, protein stability, and recruitment of the CCAN (constitutive centromere-associated network). Here, we discuss the PTMs of CENP-A and their biological relevance.

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“…Instead, it takes place in humans during early G1 phase, following the loss of CDK activity (Jansen et al 2007;Silva et al 2012;Spiller et al 2017). In most vertebrates, the Mis18 complex of Mis18α, Mis18β and Mis18BP1, apparently licenses the centrochromatin for CENP-A deposition (Fujita et al 2007;Barnhart et al 2011 The ability to engineer the alphoid tetO HAC centromeric chromatin by targeting tetracycline repressor fusion chimeras make this a suitable system to dissect the epigenetic factors that control kinetochore maintenance and function at an established centromere (Nakano et al 2008) (Table 1).…”

Section: Heterochromatin Versus Centrochromatin In Centromere Assemblmentioning

confidence: 99%

Using human artificial chromosomes to study centromere assembly and function

et al. 2017

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Abstract:Centromeres are the site of assembly of the kinetochore, which directs chromosome segregation during cell division. Active centromeres are characterized by the presence of nucleosomes containing CENP-A and a specific chromatin environment that resembles that of active genes. Recent work using Human Artificial Chromosomes (HAC) sheds light on the fine balance of different histone post-translational modifications and transcription that exists at centromeres for kinetochore assembly and maintenance. Here, we review the use of HAC technology to understand centromere assembly and function. We put particular emphasis on studies using the alphoidtetO HAC, whose centromere can be specifically modified for epigenetic engineering studies. Author Comments:We suggest Professor Erich Nigg as an Editor (not found in the "Request Editor" list), who invited us to write this review.Response to Reviewers: Comments for the Author:Reviewer #1: Since there has been significant progress over the last few years with regards to HAC technology, particularly with alphoidtetO HACs, a review on this topic would be welcomed in the field, especially by these authors, who are world experts on Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationthis topic. The review is mostly satisfying, but I would suggest two areas where the authors would be well served to make additions/changes to avoid disappointing readers hoping for more focus/organization/clarity. First, since the goal of this review is to "review the use of HAC technology to understand centromere assembly and function", it would be especially helpful if the authors summarized the evolution of HAC technology and the findings that came from targeting different tetR fusion proteins to the alphoidtetO HACs (probably most effectively in a table or schematic).We thank the reviewer for the thoughtful review of our MS. Following the reviewer´s advice, a table has been added explaining the findings that came from the alphoidtetO HAC studies in a timeline manner (Table 1).Second, more discussion on the pitfalls of current HACs would be desirable (currently only a couple sentences is mentioned in the future directions). From how it is written they sound so great that a reader would probably wonder why they are not used more widely in the research lab and/or clinic. There are problems with them, and it would be more clear and interesting, in my opinion, if more of the problems were laid out/challenges addressed.A description of limitations of the HAC technology have been added in the text, first limitations for HAC clinical use (p. 8-9) and additional limitations that should be overcome in the final remarks (p. 23). Some other changes that I'd suggest:1. It's confusing to refer to the same DNA as "alpha satellite", "α-satellite", and "alpha-satellite" throughout the review (most notably in the first two lines of the second paragraph). Why not just refer to it as "α-satellite" DNA?We changed the term to α-satellite DNA throughout the text to maintain consist...

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Molecular basis for Cdk1‐regulated timing of Mis18 complex assembly and CENP‐A deposition

Cited by 55 publications

References 33 publications

Posttranslational mechanisms controlling centromere function and assembly

Posttranslational mechanisms controlling centromere function and assembly

Posttranslational modifications of CENP-A: marks of distinction

Using human artificial chromosomes to study centromere assembly and function

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