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 48 publications

(76 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

View full text Add to dashboard Cite

show abstract

“…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 of C. elegans CENP-A Interacts with KNL-2 and is Essential for Centromeric Chromatin Assembly

Groot

Houston

Davis

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 48 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 of C. elegans CENP-A Interacts with KNL-2 and is Essential for Centromeric Chromatin Assembly

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

Contact Info

Product

Resources

About