Mechanism of centromere recruitment of the CENP-A chaperone HJURP and its implications for centromere licensing

Pan, Dongqing; Walstein, Kai; Take, Annika; Bier, David; Kaiser, Nadine; Musacchio, Andrea

doi:10.1038/s41467-019-12019-6

Cited by 55 publications

(77 citation statements)

References 86 publications

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“…In vertebrates, CENP-A incorporation into chromatin is mediated by a specific chaperone, HJURP (Dunleavy et al, 2009;Foltz et al, 2009;Bernad et al, 2011) that forms a complex with acetylated histone H4 (Sullivan & Karpen, 2004;Bailey et al, 2016;Shang et al, 2016). The HJURP/CENP-A/H4 complex is directed to the centromere via the Mis18 complex (Barnhart et al, 2011;Wang et al, 2014;Nardi et al, 2016;Pan et al, 2019), an octameric protein complex (M18BP1 and Mis18a/b subunit) that licenses new CENP-A deposition (Moree et al, 2011;Dambacher et al, 2012). How the Mis18 complex recognizes centromeres is still a matter of investigation, but M18BP1 and Mis18b were shown to interact with the Cterminal domain of CENP-C (Moree et al, 2011;Dambacher et al, 2012;Stellfox et al, 2016;Pan et al, 2017) or directly with CENP-A in both chicken (Hori et al, 2017) and frogs (French et al, 2017) (although the residue involved in this interaction is missing in humans).…”

Section: Introductionmentioning

confidence: 99%

A genetic memory initiates the epigenetic loop necessary to preserve centromere position

et al. 2020

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Centromeres are built on repetitive DNA sequences (CenDNA) and a specific chromatin enriched with the histone H3 variant CENP-A, the epigenetic mark that identifies centromere position. Here, we interrogate the importance of CenDNA in centromere specification by developing a system to rapidly remove and reactivate CENP-A (CENP-A OFF/ ON). Using this system, we define the temporal cascade of events necessary to maintain centromere position. We unveil that CENP-B bound to CenDNA provides memory for maintenance on human centromeres by promoting de novo CENP-A deposition. Indeed, lack of CENP-B favors neocentromere formation under selective pressure. Occasionally, CENP-B triggers centromere re-activation initiated by CENP-C, but not CENP-A, recruitment at both ectopic and native centromeres. This is then sufficient to initiate the CENP-A-based epigenetic loop. Finally, we identify a population of CENP-A-negative, CENP-B/C-positive resting CD4 + T cells capable to re-express and reassembles CENP-A upon cell cycle entry, demonstrating the physiological importance of the genetic memory.

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Section: Introductionmentioning

confidence: 99%

A genetic memory initiates the epigenetic loop necessary to preserve centromere position

et al. 2020

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“…The Mis18 complex is composed of Mis18 and/or KNL-2/M18BP1, depending on the species: Mis18α, Mis18β & M18BP1 in humans (Fujita et al, 2007); Mis18 only in S. pombe (Hayashi et al, 2004;Pidoux et al, 2009;Williams et al, 2009); KNL-2 only in C. elegans (Maddox et al, 2007) and Arabidopsis (Lermontova et al, 2013). S. pombe Mis18 and human Mis18a/b interact with HJURP/Scm3 in vitro (Pan et al, 2019;Pidoux et al, 2009;Wang et al, 2014) and Mis18 complex-mediated CENP-A recruitment can be bypassed by artificial tethering of HJURP/Scm3 to chromatin (Barnhart et al, 2011;Foltz et al, 2009;Ohzeki et al, 2012). In human cells, centromere localization of the Mis18 complex precedes that of the CENP-A-H4-HJURP prenucleosomal complex during mitotic exit-coupled new CENP-A chromatin assembly (Foltz et al, 2009;Jansen et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The N-terminal Tail ofC. elegansCENP-A Interacts with KNL-2 and is Essential for Centromeric Chromatin Assembly

Groot

Houston

Davis

et al. 2020

Preprint

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Centromeres are epigenetically defined by the presence of the centromere-specific histone H3 variant CENP-A. A specialized loading machinery, including the histone chaperone HJURP/Scm3, participates in CENP-A nucleosome assembly. However, Scm3/HJURP is missing from multiple lineages, including nematodes, which rely on a CENP-A-dependent centromere. Here, we show that the extended N-terminal tail of C. elegans CENP-A contains a predicted structured region that is essential for centromeric chromatin assembly. Removal of this region of the CENP-A N-Tail prevents loading, resulting in failure of kinetochore assembly and defective chromosome condensation. By contrast, the N-Tail mutant CENP-A localizes normally in the presence of endogenous CENP-A. The portion of the N-Tail containing the predicted structured region binds to KNL-2, a conserved SANTA and Myb domain-containing protein (referred to as M18BP1 in vertebrates), that is specifically involved in CENP-A chromatin assembly. This direct interaction is conserved in the related nematode C. briggsae, despite divergence of the N-Tail and KNL-2 primary sequences. Thus, the extended N-Tail of CENP-A is essential for CENP-A chromatin assembly in C. elegans and partially substitutes for the function of Scm3/HJURP, in that it mediates an interaction of the specialized histone fold of CENP-A with KNL-2. These results highlight an evolutionary variation on centromeric chromatin assembly in the absence of a dedicated CENP-A-specific chaperone/targeting factor of the Scm3/HJURP family.

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“…Binding of HJURP is proposed to disrupt the Mis18 complex leading to removal of Mis18α [113] and of M18BP1 [105], thereby restricting CENP-A deposition to a single event per cell cycle. Contrarily, recent work proposes that HJURP does not cause dissociation of the Mis18 complex and that HJURP is not dimerized in the process of CENP-A deposition [116], as previously suggested [117]. Deposition of CENP-A:H4 dimers into a homotypic octameric nucleosome is proposed to be achieved through two nearby Mis18:HJURP complexes depositing individual CENP-A:H4 dimers that are tetramerized into the same nucleosome [116].…”

Section: Temporal Regulation Of Cenp-a Deposition: Precision In Actionmentioning

confidence: 79%

“…Furthermore, as mentioned above, tethering HJURP to an ectopic non-centromeric locus is sufficient to induce incorporation of CENP-A into the chromatin at this site and leads to nucleation of a functional de novo kinetochore [31,32]. HJURP binds a single CENP-A-histone:H4 heterodimer [120] and is thought to achieve the assembly of homotypic octameric CENP-A nucleosomes via dimerization of HJURP through its C-terminal domain [117] or through two nearby Mis18:HJURP complexes, each depositing individual CENP-A:H4 dimers that are tetramerized into the same nucleosome [116].…”

Section: Global Regulation Restricts Cenp-a Assembly To Early G1mentioning

confidence: 99%

Guarding the Genome: CENP-A-Chromatin in Health and Cancer

Mahlke

Nechemia-Arbely

2020

Genes

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Faithful chromosome segregation is essential for the maintenance of genomic integrity and requires functional centromeres. Centromeres are epigenetically defined by the histone H3 variant, centromere protein A (CENP-A). Here we highlight current knowledge regarding CENP-A-containing chromatin structure, specification of centromere identity, regulation of CENP-A deposition and possible contribution to cancer formation and/or progression. CENP-A overexpression is common among many cancers and predicts poor prognosis. Overexpression of CENP-A increases rates of CENP-A deposition ectopically at sites of high histone turnover, occluding CCCTC-binding factor (CTCF) binding. Ectopic CENP-A deposition leads to mitotic defects, centromere dysfunction and chromosomal instability (CIN), a hallmark of cancer. CENP-A overexpression is often accompanied by overexpression of its chaperone Holliday Junction Recognition Protein (HJURP), leading to epigenetic addiction in which increased levels of HJURP and CENP-A become necessary to support rapidly dividing p53 deficient cancer cells. Alterations in CENP-A posttranslational modifications are also linked to chromosome segregation errors and CIN. Collectively, CENP-A is pivotal to genomic stability through centromere maintenance, perturbation of which can lead to tumorigenesis.

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Mechanism of centromere recruitment of the CENP-A chaperone HJURP and its implications for centromere licensing

Cited by 55 publications

References 86 publications

A genetic memory initiates the epigenetic loop necessary to preserve centromere position

A genetic memory initiates the epigenetic loop necessary to preserve centromere position

The N-terminal Tail ofC. elegansCENP-A Interacts with KNL-2 and is Essential for Centromeric Chromatin Assembly

Guarding the Genome: CENP-A-Chromatin in Health and Cancer

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