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The Role of Centromeres in Genome Stability
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The Role of Centromeres in Genome Stability

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 23930

Special Issue Editor

Dr. Simona Giunta

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Guest Editor
Laboratory of Chromosomal and Cell Biology, The Rockefeller University, New York, NY 10065, USA
Interests: DNA damage repair; genome stability; repetitive DNA; human chromosomes

Special Issue Information

Dear Colleagues,

Centromeres are fascinating chromosomal loci required for the faithful transmission of genetic information at each cellular generation. In most plants and animals, centromeres are made up of highly repetitive sequences, are epigenetically specified by a specialized chromatin status, including the presence of a centromere-specific H3 histone variant, and are essential to support the formation of the kinetochore and bind the spindle microtubules in mitosis to enable chromosome segregation.

Contrary to initial thoughts, recent evidence has pointed at important DNA-based transactions happening at centromeres. While gene-poor, the repeats are not silent. Long non-coding RNA transcripts originated from centromeres bear unexpected roles in stabilizing proteins binding to the region and promote kinetochore function. Similarly, centromere repeats are not as stable as previously thought. Recent evidence indicates that centromere alpha-satellite DNA suffers from instability due to recombination, especially enhanced in the context of cancer and cellular senescence. These and other novel paradigms in the centromere field raise interesting questions on how transcription, repair, and other processes impact centromere stability and function and how the deterioration of centromere repeats integrity may be implicated in human health and disease.

In this Special Issue of Genes, I want to extend an invitation to reviews as well as original research articles on the current state of affair in centromere genomics, transcriptomics and molecular mechanisms operating at the centromere repeats. I am especially interested in contributions that utilize novel experimental methods, including computational approaches, that bring forward alternative hypotheses to the previously described paradoxes in centromere biology, highlighting centromere association with genome and chromosome stability, and/or contributing to further our understanding of centromeres’ role in disease. I will, however, consider any manuscript that advances the understanding of these “dark” regions of our genome.

Dr. Simona Giunta
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • centromere
  • repetitive DNA
  • chromosomes
  • epigenetic
  • transcription
  • genome stability

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Published Papers (4 papers)

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Review

28 pages, 1816 KiB  
Review
Centromeres under Pressure: Evolutionary Innovation in Conflict with Conserved Function
by Elisa Balzano and Simona Giunta
Genes 2020, 11(8), 912; https://doi.org/10.3390/genes11080912 - 10 Aug 2020
Cited by 27 | Viewed by 4906
Abstract
Centromeres are essential genetic elements that enable spindle microtubule attachment for chromosome segregation during mitosis and meiosis. While this function is preserved across species, centromeres display an array of dynamic features, including: (1) rapidly evolving DNA; (2) wide evolutionary diversity in size, shape [...] Read more.
Centromeres are essential genetic elements that enable spindle microtubule attachment for chromosome segregation during mitosis and meiosis. While this function is preserved across species, centromeres display an array of dynamic features, including: (1) rapidly evolving DNA; (2) wide evolutionary diversity in size, shape and organization; (3) evidence of mutational processes to generate homogenized repetitive arrays that characterize centromeres in several species; (4) tolerance to changes in position, as in the case of neocentromeres; and (5) intrinsic fragility derived by sequence composition and secondary DNA structures. Centromere drive underlies rapid centromere DNA evolution due to the “selfish” pursuit to bias meiotic transmission and promote the propagation of stronger centromeres. Yet, the origins of other dynamic features of centromeres remain unclear. Here, we review our current understanding of centromere evolution and plasticity. We also detail the mutagenic processes proposed to shape the divergent genetic nature of centromeres. Changes to centromeres are not simply evolutionary relics, but ongoing shifts that on one side promote centromere flexibility, but on the other can undermine centromere integrity and function with potential pathological implications such as genome instability. Full article
(This article belongs to the Special Issue The Role of Centromeres in Genome Stability)
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23 pages, 2010 KiB  
Review
Centromeric Transcription: A Conserved Swiss-Army Knife
by Ganesan Arunkumar and Daniël P. Melters
Genes 2020, 11(8), 911; https://doi.org/10.3390/genes11080911 - 9 Aug 2020
Cited by 25 | Viewed by 6012
Abstract
In most species, the centromere is comprised of repetitive DNA sequences, which rapidly evolve. Paradoxically, centromeres fulfill an essential function during mitosis, as they are the chromosomal sites wherein, through the kinetochore, the mitotic spindles bind. It is now generally accepted that centromeres [...] Read more.
In most species, the centromere is comprised of repetitive DNA sequences, which rapidly evolve. Paradoxically, centromeres fulfill an essential function during mitosis, as they are the chromosomal sites wherein, through the kinetochore, the mitotic spindles bind. It is now generally accepted that centromeres are transcribed, and that such transcription is associated with a broad range of functions. More than a decade of work on this topic has shown that centromeric transcripts are found across the eukaryotic tree and associate with heterochromatin formation, chromatin structure, kinetochore structure, centromeric protein loading, and inner centromere signaling. In this review, we discuss the conservation of small and long non-coding centromeric RNAs, their associations with various centromeric functions, and their potential roles in disease. Full article
(This article belongs to the Special Issue The Role of Centromeres in Genome Stability)
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24 pages, 2754 KiB  
Review
Guarding the Genome: CENP-A-Chromatin in Health and Cancer
by Megan A. Mahlke and Yael Nechemia-Arbely
Genes 2020, 11(7), 810; https://doi.org/10.3390/genes11070810 - 16 Jul 2020
Cited by 40 | Viewed by 7860
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Role of Centromeres in Genome Stability)
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19 pages, 2592 KiB  
Review
Epigenetics as an Evolutionary Tool for Centromere Flexibility
by Laura Leo, Marcella Marchetti, Simona Giunta and Laura Fanti
Genes 2020, 11(7), 809; https://doi.org/10.3390/genes11070809 - 16 Jul 2020
Cited by 8 | Viewed by 4350
Abstract
Centromeres are the complex structures responsible for the proper segregation of chromosomes during cell division. Structural or functional alterations of the centromere cause aneuploidies and other chromosomal aberrations that can induce cell death with consequences on health and survival of the organism as [...] Read more.
Centromeres are the complex structures responsible for the proper segregation of chromosomes during cell division. Structural or functional alterations of the centromere cause aneuploidies and other chromosomal aberrations that can induce cell death with consequences on health and survival of the organism as a whole. Because of their essential function in the cell, centromeres have evolved high flexibility and mechanisms of tolerance to preserve their function following stress, whether it is originating from within or outside the cell. Here, we review the main epigenetic mechanisms of centromeres’ adaptability to preserve their functional stability, with particular reference to neocentromeres and holocentromeres. The centromere position can shift in response to altered chromosome structures, but how and why neocentromeres appear in a given chromosome region are still open questions. Models of neocentromere formation developed during the last few years will be hereby discussed. Moreover, we will discuss the evolutionary significance of diffuse centromeres (holocentromeres) in organisms such as nematodes. Despite the differences in DNA sequences, protein composition and centromere size, all of these diverse centromere structures promote efficient chromosome segregation, balancing genome stability and adaptability, and ensuring faithful genome inheritance at each cellular generation. Full article
(This article belongs to the Special Issue The Role of Centromeres in Genome Stability)
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