Phosphorylation of CENP-A on serine 7 does not control centromere function

Barra, Viviana; Logsdon, Glennis A.; Scelfo, Andrea; Hoffmann, Sebastian; Hervé, Solène; Aslanian, Aaron; Nechemia-Arbely, Yael; Cleveland, Don W.; Black, Ben E.; Fachinetti, Daniele

doi:10.1038/s41467-018-08073-1

Cited by 17 publications

(13 citation statements)

References 47 publications

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“…EdU click labeling was performed using Click-iT â labeling technologies (Thermo Fisher Scientific), and colony formation assays were performed as previously described (Barra et al, 2019).…”

Section: Generation Of Stable Cell Linesmentioning

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: Generation Of Stable Cell Linesmentioning

confidence: 99%

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

et al. 2020

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“…The N-terminal tail of CENP-A is considered to be flexible and unstructured but plays an important role in centromere biology [50][51][52][53][54]. It contributes to the interactions with the kinetochore proteins CENP-B, CENP-C, and CENP-T [50,51,55,56], although there may be species-specific differences in how these proteins interact.…”

Section: Discussionmentioning

confidence: 99%

Transgenerational inheritance of centromere identity requires the CENP-A N-terminal tail in the C. elegans maternal germ line

et al. 2021

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Centromere protein A (CENP-A) is a histone H3 variant that defines centromeric chromatin and is essential for centromere function. In most eukaryotes, CENP-A-containing chromatin is epigenetically maintained, and centromere identity is inherited from one cell cycle to the next. In the germ line of the holocentric nematode Caenorhabditis elegans, this inheritance cycle is disrupted. CENP-A is removed at the mitosis-to-meiosis transition and is reestablished on chromatin during diplotene of meiosis I. Here, we show that the N-terminal tail of CENP-A is required for the de novo establishment of centromeres, but then its presence becomes dispensable for centromere maintenance during development. Worms homozygous for a CENP-A tail deletion maintain functional centromeres during development but give rise to inviable offspring because they fail to reestablish centromeres in the maternal germ line. We identify the N-terminal tail of CENP-A as a critical domain for the interaction with the conserved kinetochore protein KNL-2 and argue that this interaction plays an important role in setting centromere identity in the germ line. We conclude that centromere establishment and maintenance are functionally distinct in C. elegans.

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“…CENP-A function is also regulated by posttranslational modifications to the CENP-A histone itself. Several sites of posttranslational modification have been identified for CENP-A, including α-amino trimethylation [ 180 ], Ser7 phosphorylation [ 181 , 182 ], Ser16/18 phosphorylation [ 161 , 183 ], Ser68 phosphorylation [ 184 , 185 ], Lys124 ubiquitination [ 185 , 186 , 187 , 188 ], Lys124 acetylation [ 50 , 189 ], and Lys124 monomethylation [ 189 ], some of which are emerging as important regulators of CENP-A deposition and function within the centromere [reviewed at Srivastava and Foltz [ 190 ]].…”

Section: Perturbations In Cenp-a Posttranslational Modifications mentioning

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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Phosphorylation of CENP-A on serine 7 does not control centromere function

Cited by 17 publications

References 47 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

Transgenerational inheritance of centromere identity requires the CENP-A N-terminal tail in the C. elegans maternal germ line

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

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