Using human artificial chromosomes to study centromere assembly and function
- 1k Downloads
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.
KeywordsHuman artificial chromosomes Centromere Kinetochore CENP-A Mitosis
Compliance with ethical standards
This work was supported by the Wellcome Trust, of which W.C.E. is a Principal Research Fellow (grant number 073915). O.M. was funded by the European Molecular Biology Organization (long-term EMBO fellowship; ALTF-453-2012). The Intramural Research Program of the NIH, NCI Center for Cancer Research (V.L. and N.K.) and MEXT KAKENHI grant numbers 23247030, 23114008 and the Kazusa DNA Research Institute Foundation (H.M.).
Conflict of interests
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- Bergmann JH, Martins NM, Larionov V, Masumoto H, Earnshaw WC (2012b) HACking the centromere chromatin code: insights from human artificial chromosomes Chromosome research. an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 20:505–519. doi: 10.1007/s10577-012-9293-0 CrossRefGoogle Scholar
- Blower MD, Sullivan BA, Karpen GH (2002) Conserved organization of centromeric chromatin in flies and humans Developmental. Cell 2:319–330Google Scholar
- Brown KE, Barnett MA, Burgtorf C, Shaw P, Buckle VJ, Brown WR (1994) Dissecting the centromere of the human Y chromosome with cloned telomeric DNA Human molecular. Genetics 3:1227–1237Google Scholar
- Cheeseman IM, Hori T, Fukagawa T, Desai A (2008) KNL1 and the CENP-H/I/K complex coordinately direct kinetochore assembly in vertebrates Molecular biology of the cell 19:587–594 doi: 10.1091/mbc.E07-10-1051
- Drinnenberg IA, de Young D, Henikoff S, Malik HS (2014) Recurrent loss of CenH3 is associated with independent transitions to holocentricity in insects eLife 3 doi: 10.7554/eLife.03676
- Henning KA, Novotny EA, Compton ST, Guan XY, Liu PP, Ashlock MA (1999) Human artificial chromosomes generated by modification of a yeast artificial chromosome containing both human alpha satellite and single-copy DNA sequences. Proc Natl Acad Sci U S A 96:592–597PubMedPubMedCentralCrossRefGoogle Scholar
- Ikeno M, Masumoto H, Okazaki T (1994) Distribution of CENP-B boxes reflected in CREST centromere antigenic sites on long-range alpha-satellite DNA arrays of human chromosome 21 Human molecular. Genetics 3:1245–1257Google Scholar
- Kim JH et al. (2016) Development of a novel HAC-based "gain of signal" quantitative assay for measuring chromosome instability (CIN) in cancer cellsGoogle Scholar
- Kononenko AV et al. (2014) A portable BRCA1-HAC (human artificial chromosome) module for analysis of BRCA1 tumor suppressor function Nucleic acids research 42 doi: 10.1093/nar/gku870
- Molina O, Carmena M, Maudlin IE, Earnshaw WC (2016a) PREditOR: a synthetic biology approach to removing heterochromatin from cells Chromosome research. an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 24:495–509. doi: 10.1007/s10577-016-9539-3 CrossRefGoogle Scholar
- Moralli D, Monaco ZL (2015) Developing de novo human artificial chromosomes in embryonic stem cells using HSV-1 amplicon technology Chromosome research : an international journal on the molecular. supramolecular and evolutionary aspects of chromosome biology 23:105–110. doi: 10.1007/s10577-014-9456-2 CrossRefGoogle Scholar
- Ohzeki J, Larionov V, Earnshaw WC, Masumoto H (2015) Genetic and epigenetic regulation of centromeres: a look at HAC formation Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome. Biology 23:87–103. doi: 10.1007/s10577-015-9470-z Google Scholar
- Oshimura M, Uno N, Kazuki Y, Katoh M, Inoue T (2015) A pathway from chromosome transfer to engineering resulting in human and mouse artificial chromosomes for a variety of applications to bio-medical challenges Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome. Biology 23:111–133. doi: 10.1007/s10577-014-9459-z Google Scholar
- Saffery R, Irvine DV, Griffiths B, Kalitsis P, Wordeman L, Choo KH (2000) Human centromeres and neocentromeres show identical distribution patterns of >20 functionally important kinetochore-associated proteins Human molecular. Genetics 9:175–185Google Scholar
- Schalch T, Steiner FA (2016) Structure of centromere chromatin: from nucleosome to chromosomal architecture Chromosoma doi: 10.1007/s00412-016-0620-7
- Spiller F, Medina-Pritchard B, Abad MA, Wear MA, Molina O, Earnshaw WC, Jeyaprakash AA (2017) Molecular basis for Cdk1-regulated timing of Mis18 complex assembly and CENP-A deposition. EMBO Rep. doi: 10.15252/embr.201643564
- Stimpson KM, Matheny JE, Sullivan BA (2012) Dicentric chromosomes: unique models to study centromere function and inactivation Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome. Biology 20:595–605. doi: 10.1007/s10577-012-9302-3 Google Scholar
- Sullivan LL, Boivin CD, Mravinac B, Song IY, Sullivan BA (2011) Genomic size of CENP-A domain is proportional to total alpha satellite array size at human centromeres and expands in cancer cells Chromosome research. an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 19:457–470. doi: 10.1007/s10577-011-9208-5 CrossRefGoogle Scholar