Dicentric chromosomes: Unique models to study centromere function and inactivation

Article (PDF Available)inChromosome Research 20(5):595-605 · July 2012with33 Reads
DOI: 10.1007/s10577-012-9302-3 · Source: PubMed
Dicentric chromosomes are products of genome rearrangement that place two centromeres on the same chromosome. Depending on the organism, dicentric stability varies after formation. In humans, dicentrics occur naturally in a substantial portion of the population and usually segregate successfully in mitosis and meiosis. Their stability has been attributed to inactivation of one of the two centromeres, creating a functionally monocentric chromosome that can segregate normally during cell division. The molecular basis for centromere inactivation is not well understood, although studies in model organisms and in humans suggest that genomic and epigenetic mechanisms can be involved. Furthermore, constitutional dicentric chromosomes ascertained in patients presumably represent the most stable chromosomes, so the spectrum of dicentric fates, if it exists, is not entirely clear. Studies of engineered or induced dicentrics in budding yeast and plants have provided significant insight into the fate of dicentric chromosomes. And, more recently, studies have shown that dicentrics in humans can also undergo multiple fates after formation. Here, we discuss current experimental evidence from various organisms that has deepened our understanding of dicentric behavior and the intriguingly complex process of centromere inactivation.
Dicentric chromosomes: unique models to study centromere
function and inactivation
Kaitlin M. Stimpson &Justyne E. Matheny &
Beth A. Sullivan
Published online: 17 July 2012
#Springer Science+Business Media B.V. 2012
Abstract Dicentric chromosomes are products of
genome rearrangement that place two centromeres on
the same chromosome. Depending on the organism,
dicentric stability varies after formation. In humans,
dicentrics occur naturally in a substantial portion of
the population and usually segregate successfully in
mitosis and meiosis. Their stability has been attributed
to inactivation of one of the two centromeres, creating
a functionally monocentric chromosome that can seg-
regate normally during cell division. The molecular
basis for centromere inactivation is not well under-
stood, although studies in model organisms and in
humans suggest that genomic and epigenetic mecha-
nisms can be involved. Furthermore, constitutional
dicentric chromosomes ascertained in patients presum-
ably represent the most stable chromosomes, so the
spectrum of dicentric fates, if it exists, is not entirely
clear. Studies of engineered or induced dicentrics in
budding yeast and plants have provided significant
insight into the fate of dicentric chromosomes. And,
more recently, studies have shown that dicentrics in
humans can also undergo multiple fates after forma-
tion. Here, we discuss current experimental evidence
from various organisms that has deepened our under-
standing of dicentric behavior and the intriguingly
complex process of centromere inactivation.
Keywords CENP-A .heterochromatin .euchromatin .
DNA methylation .deletion .fusion
5mC 5-methylcytosine
BFB Breakagefusionbridge
CDE Centromere DNA element
CEN Centromere
Centromere-specific histone H3
variant (also known as CENP-A)
CENP-A Centromere protein A
CENP-C Centromere protein C
CENP-E Centromere protein E
CentC Maize A-chromosome
centromere-specific satellite repeat
Cnp1 S. pombe CENP-A/CenH3
CRM Maize centromeric
retrotransposon element
Cse4p S. cerevisiae CENP-A/CenH3
GAL1 Galactose 1 (gene or promoter)
H3K4me2 Histone H3 dimethylated at lysine 4
H3K9ac Histone H3 acetylated at lysine 9
H3K9me2 Histone H3 dimethylated at lysine 9
H3K14ac Histone H3 acetylated at lysine 13
Chromosome Res (2012) 20:595605
DOI 10.1007/s10577-012-9302-3
Responsible Editor: Rachel ONeill and Beth Sullivan.
Kaitlin M. Stimpson and Justyne E. Matheny contributed
equally to this work.
K. M. Stimpson :J. E. Matheny :B. A. Sullivan
Institute for Genome Sciences and Policy, Duke University,
Durham, NC 27708, USA
B. A. Sullivan (*)
Department of Molecular Genetics and Microbiology,
Duke University Medical Center,
Durham, NC 27710, USA
e-mail: beth.sullivan@duke.edu
H3K27me2/me3 Histone H3 di- or tri-methylated
at lysine 27
HJURP Holliday junction protein
i(Xp) Isochromosome of the X short arm
i(Xq) Isochromosome of the X long arm
isoX/i(X) Isochromosome X
FISH Fluorescence in situ
NDJ Non-disjunction
NHEJ Non-homologous end joining
PFGE Pulsed field gel electrophoresis
PH3S10 Histone H3 phosphorylated at serine 10
ROB/rob Robertsonian translocation
TRF2 Telomere repeat-binding factor 2
ZmB Maize B-chromosome-specific
satellite repeat
The centromere is a complex chromosomal locus where
the kinetochore is formed and microtubules attach dur-
ing cell division. A major component of functional
centromeres is CENP-A/CenH3, a histone H3 variant
that replaces canonical H3 to create unique centromeric
nucleosomes (Palmer et al. 1989;Palmeretal.1991).
CENP-A physically marks centromeres by assembling
into largely homotypic nucleosomes (two copies of
CENP-A) that have a more rigid conformation than
H3-containing nucleosomes (Black and Bassett 2008;
Black et al. 2004). The centromeric chromatin of multi-
cellular eukaryotes is arranged as multiple subunits of
CENP-A nucleosomes periodically interspersed with
subunits of H3 nucleosomes that are dimethylated at
lysine 4 (H3K4me2) (Blower et al. 2002;Sullivanand
Karpen 2004). Together, physically distinct nucleo-
somes and long-range chromatin organization are
thought to create a platform for kinetochore formation
and recruitment of additional centromere and kineto-
chore proteins (Blower and Karpen 2001; Foltz et al.
2006;Horietal.2008). In general, each chromosome
contains a single region of centromeric DNA where the
centromere and kinetochore are assembled. However,
genome rearrangements can lead to fusion of two dif-
ferent chromosomes, often resulting in a dicentric chro-
mosome on which two centromeres are physically
linked. The prevailing view of dicentric behavior, first
described in maize by Barbara McClintock, is that they
are inherently unstable, often undergoing successive
rounds of anaphase bridge formation and breakage
(McClintock 1939; McClintock 1941). Indeed, this
model holds true for budding yeast and Drosophila in
which dicentrics are largely unstable and lead to broken
and rearranged chromosomes (Hill and Bloom 1987;
Hill and Bloom 1989; Thrower and Bloom 2001;
Thrower et al. 2003). However, it has been known for
some time in mammals, and more recently in several
model organisms, that dicentric chromosomes can be
quite stable in mitosis. In fact, dicentric human chromo-
somes can be inherited through meiosis. Such stability
has been attributed to the phenomenon of centromere
inactivation, a poorly understood process by which one
of the centromeres becomes nonfunctional or inactive
(Earnshaw and Migeon 1985; Sullivan and Schwartz
1995). Consequently, the structurally dicentric chromo-
some behaves and segregates as a functionally mono-
centric chromosome during cell division.
Our understanding of centromere inactivation comes
largely from observational studies in humans. Cytolog-
ically, inactive centromeres lack a constricted appear-
ance on metaphase chromosomes. In addition, a variety
of essential centromere and kinetochore proteins and
chromosomal and chromatin proteins are absent from
inactive centromeres (Earnshaw and Migeon 1985;
Sullivan and Schwartz 1995;Pageetal.1995b;Craig
et al. 2003). Beyond these cytological observations,
however, the molecular basis of centromere inactivation
has remained unclear for decades. Testing mechanisms
of centromere inactivation has proven difficult for sev-
eral reasons. First, it was not appreciated until recently
that centromere inactivation is a major mechanism of
dicentric stability in model organisms. Furthermore,
there are few experimental systems to produce de novo
dicentric human chromosomes, so it has been difficult to
capture the process of inactivation in human cells where
it is a common mechanism of dicentric stabilization.
It has been known for two decades that inactive
centromeres of dicentric chromosomes lack key centro-
mere and kinetochore proteins, such as CENP-A,
CENP-C, and CENP-E (Earnshaw et al. 1989; Sullivan
and Schwartz 1995). Additionally, they lack a defined
primary constriction on metaphase chromosomes and
morphologically resemble chromosome arms. Thus,
centromere inactivation is predicted to involve exclu-
sion of centromere proteins and chromatin remodeling
so that the two centromeres on the dicentric become
functionally distinct. The molecular basis of dicentric
stability is further complicated by observations that
596 K.M. Stimpson et al.
dicentrics behave in different ways immediately after
formation. Most undergo centromere inactivation, but
some remain functionally dicentric (Sullivan and
Schwartz 1995; Higgins et al. 2005; Page and Shaffer
1998; Sullivan and Willard 1998; Stimpson et al. 2010).
The molecular basis for why dicentrics behave in such
variable ways remains an area of great interest. In this
review, we will discuss dicentric chromosome behavior
in various organisms, mechanisms by which these
dicentrics are stabilized, and current knowledge regarding
features of inactive centromeres.
Dicentrics in the budding yeast Saccharomyces
Studies in the budding yeast S. cerevisiae were among the
first to demonstrate both the mitotic instability and fate of
dicentric chromosomes in a model organism other than
maize. Yeast centromeres contain distinct structural ele-
ments CDEI, CDEII, and CDEIII that are absolutely
required for proper centromere assembly and function.
Dicentrics in yeast have been engineered using (1) non-
essential minichromosomes; (2) endogenous chromo-
somes containing an extra-conditional centromere
encoded on an integrated GAL1-CEN cassette; (3) endog-
enous, conditional centromeres (those flanked by GAL1
promoter sequences); (4) spontaneous or induced loss of
specific markers integrated into the genome; or (5) specific
kinetochore, DNA replication, or DNA damage mutants
(Fig. 1). The minichromosome studies revealed that muta-
tions in CDEII or CDEIII could effectively stabilize the
dicentrics so that they functioned as monocentric struc-
tures (Koshland et al. 1987). Additionally, if inter-
centromeric distances were decreased, both centromeres
could remain functional if they co-oriented to the same
spindle poles and/or behaved cooperatively (Fig. 1b).
Dicentrics created using endogenous chromosomes
have revealed more complex mitotic behaviors. In assays
using the GAL1-CEN construct, the second CEN was
kept inactive by driving GAL1 transcription through the
cassette. However, when GAL1 transcription was turned
off, leading to activation of the second centromere, the
dicentric chromosome became unstable during cell divi-
sion, resulting in chromosome lag and DNA breakage via
breakagefusionbridge (BFB) cycles. However, the
dicentrics could be stabilized if one of the centromeres
underwent breakage and recombination that physically
deleted one centromere (Hill and Bloom 1989; Jager and
Philippsen 1989)(Fig.1b). More recently, this assay was
modified so that the GAL1-CEN strain was combined
with a conditional Rap1 mutant allele. Rap1 is important
for telomere stability and prevents NHEJ of chromosome
ends. The Rap1 conditional mutation produced chromo-
some end-fusions and those between a normal chromo-
some and a GAL1-CEN marked chromosome were
selected for analysis (Pobiega and Marcand 2010). Upon
induction of end-fusions, the GAL1-CEN was activated
and dicentric behavior and fate evaluated. A little over
half of the fusions were unstable and resulted in cell death
since the cells were unable to complete cytokinesis.
However, in cells that did not die (40 %), the dicentrics
had broken at the site of telomere fusion, resulting in
liberation of each parental chromosome involved in the
rearrangement (Fig. 1c).
Other studies of dicentric budding yeast chromo-
somes have revealed even more complex means of
reducing the unstable dicentric to a monocentric state.
Repeated BFB cycles lead to multiple secondary
rearrangements (Pennaneach and Kolodner 2009)
(Fig. 1d). The dicentrics can break at repetitive ele-
ments and acquire other chromosomal sequences,
yielding a healed chromosome with partial duplica-
tions or amplifications. If repetitive elements are pres-
ent between the two centromeres, the dicentric can
also break and non-reciprocally translocate to another
chromosome. Finally, broken dicentrics can form cir-
cular chromosomes if the site of interstitial breakage
fuses to the end of the same chromosome (Fig. 1d).
Taken together, existing data from multiple groups
emphasize that dicentric chromosomes in budding
yeast are generally very unstable and are primarily
associated with secondary rearrangement and cell
Dicentrics in fission yeast Schizosaccharomyces
The fission yeast S. pombe contains three chromo-
somes (I, II, and III), and each centromere is organized
as a unique central domain containing CenH3 chro-
matin flanked by shared repetitive sequences that are
packaged into heterochromatin. Dicentrics have not
been reported to occur naturally in this organism, but
because of the similarities in centromere organization
between S. pombe and larger eukaryotes, a recent
study has engineered dicentric chromosomes between
Dicentric chromosome behavior 597
chromosomes II and III using site-specific or meiotic
recombination (Sato et al. 2012). The formation of
dicentrics were tracked using high molecular weight
pulsed field gel electrophoresis (PFGE), since the S.
pombe chromosomes can be resolved as three distinct
electrophoretic entities. The PFGE karyotypes of
strains containing dicentrics showed two bands, one
representing the normal chromosome I and a larger
band that was the product of fusion between chromo-
somes II and III. Like dicentrics in budding yeast, the
majority (99 %) of cells containing dicentrics died.
Surprisingly, though, the defects were not due to
chromosome missegregation or breakage, because
the cells arrested indefinitely in interphase (Fig. 2a).
This result suggested that dicentrics typically trigger
DNA damage and replication cell cycle checkpoints
and not checkpoints associated with improper spindle
dynamics or faulty chromosome segregation during
cell division.
Although the majority of cells with dicentrics were
arrested or died, it was noted that a small proportion
(~1 %) of dicentrics were stably maintained. Within
this population, about 10 % of the dicentrics were
stabilized by a breakage event that split the dicentric,
Fig. 1 Dicentric chromosome fate in the budding yeast S.
cerevisiae. aCircular supernumerary minichromosomes con-
taining two centromere regions (red) are stabilized by deletion
of one centromere or cooperation of the two centromeres if
closely spaced. The majority of dicentric minichromosomes
undergo non-disjunction (NDJ) events, leading to chromosome
loss. bDicentrics can be formed by insertion of GAL1-CEN
cassette (black) onto endogenous chromosomes. The second
centromere is kept inactive by GAL1 transcription. When tran-
scription is turned off, both centromeres are active and the
dicentric can be stabilized if one centromere is deleted or both
co-orient to the same spindle pole. cDicentrics can also be
formed by telomere fusion after an endogenous centromere of
one chromosome is flanked by GAL1 promoter sequences
(black). Like in (b), the second flanked centromere is kept
inactive by GAL1 transcription, but after telomere fusion to
create the dicentric, transcription is turned off. The dicentrics
can be stabilized if breakage occurs at the telomeric sequences
(orange), liberating the two chromosomes. dDicentric chromo-
some breakage is common in budding yeast, often leading to
secondary rearrangements such as non-reciprocal translocations
with other chromosomes. Alternatively, after breakage, the ends
of the derivative chromosome may fuse, creating a circular
monocentric chromosome
598 K.M. Stimpson et al.
returning the karyotype to three chromosomes, as
denoted by the reappearance of three normal-sized
chromosomal bands on agarose gels (Fig. 2a). Another
~10 % of the dicentrics remained fused, and the cells
divided normally. These dicentrics were stabilized be-
cause one of the two centromeres had been physically
deleted. Notably, these two categories of stable fission
yeast dicentrics indicate that ~30 % of the dicentrics
are stabilized by mechanisms that have also been
observed primarily in budding yeast. Intriguingly,
however, two thirds of dicentrics were stabilized by
epigenetic mechanisms (Sato et al. 2012). The central
core regions of the inactive centromeres no longer
contained Cnp1/CENP-A/CenH3 and instead became
enriched for H3K9me2, a heterochromatin-associated
histone modification, and depleted for the euchromatic
acetylated histones H3K9ac and H3K14ac. None of
the epigenetically inactivated centromeres showed ev-
idence of DNA changes (deletions or mutations).
These studies are exciting because they provide evi-
dence in a unicellular model organism for epigenetic
centromere inactivation that was previously thought to
only occur in larger multi-cellular organisms. The
results also raise the question of how the cell identifies
a chromosome with two centromeres and suspends the
cell cycle before mitosis even occurs. Finally, these
studies leave open the possibility that other organisms
may detect dicentrics prior to metaphase and could
trigger similar early cell cycle checkpoints that have
been previously underappreciated.
Fig. 2 Mechanisms of dicentric stability in fission yeast and
multicellular eukaryotes. aIn the fission yeast, S. pombe, engi-
neered dicentrics primarily result in cell cycle arrest in inter-
phase (heavy black arrow), followed by cell death. A small
proportion of cells can maintain structurally dicentric chromo-
somes because one centromere has undergone inactivation. In
~10 % of dicentrics, one centromere is physically deleted. In
another ~10 % of dicentrics, a breakage event occurs that splits
the dicentric into the two monocentric parental chromosomes.
However, two thirds of retained dicentrics undergo epigenetic
centromere inactivation in which centromeric DNA (yellow)is
retained but Cnp1/CENP-A/CENH3 (red) is absent. The chro-
matin of the inactive centromere also acquires epigenetic fea-
tures of heterochromatin. bIn plants and humans, engineered
and naturally occurring dicentric chromosomes appear to be
stabilized by two mechanisms: partial deletion of one centro-
mere or epigenetic inactivation of one centromere. In plants, the
chromatin of the inactive centromere loses CENP-A/CENH3
(red spheres), CENP-C, and PH3S10 and acquires heterochro-
matic features (orange spheres) such as H3K27me2/3 and DNA
methylation. In humans, epigenetically inactivated centromeres
lose CENP-A/CENH3 and H3K4me2 (yellow and red spheres)
Dicentric chromosome behavior 599
Dicentrics in plants
Given that dicentric chromosomes were first described in
plants, it seems fitting that much of what we know about
centromere inactivation has come from studies in maize
and other crop plants in the past 10 years. Although
McClintock first reported on the instability of dicentric
chromosomes in maize, more recently stable dicentrics
have been described in both maize and wheat (Gao et al.
2011; Han et al. 2006;Zhangetal.2010). The stability of
these chromosomes occurs by inactivation of one centro-
mere, resulting in a functionally monocentric chromo-
some. Naturally occurring and engineered dicentrics in
plants have revealed several features of inactive centro-
meres and emphasize key similarities and several differ-
ences in how centromere inactivation is achieved in plants
compared with other organisms.
Plant centromeres generally consist of a mix of both
tandem arrays of simple repeats and centromeric retro-
transposons, forming a complex chromosome locus
(Ma et al. 2007). The 20 endogenous chromosomes
in maize are typically referred to as A chromosomes.
But maize also contains small, extranumerary B chro-
mosomes. B chromosomes have aided in the study of
active and inactive centromeres due to their unique
qualities, including being entirely dispensable and
containing the B-chromosome-specific ZmB repeats.
Naturally occurring B-A translocation chromosomes
have undergone BFB cycles to yield a collection of
minichromosomes. Fluorescence in situ hybridization
(FISH) using a ZmB probe on 23 of these minichro-
mosomes revealed that five minichromosomes had
two B centromeres. However, only one centromere
was active, as determined by immunostaining for
CENH3, indicating that centromere inactivation had
occurred (Han et al. 2006). Additional studies of a
dicentric chromosome with large and small versions
of the B centromere showed that the smaller of the two
was preferentially inactivated based on immunostain-
ing for CENP-C, CENH3, and H3 phosphorylated at
Ser-10 (PH3S10) that distinguish active centromeres
(Han et al. 2009). These dicentric minichromosomes
were stable over two generations, with small centro-
meres remaining inactivated. However, when separated
by intrachromosomal recombination, the smaller centro-
meres could be reactivated, regaining the molecular
attributes of an active centromere, such as CENH3,
CENP-C, and PH3S10. Thus, these studies emphasize
the epigenetic nature of centromere inactivation, since
both inactivation and reactivation could occur without
changing the underlying DNA sequences of the small
Studies of dicentrics in S. pombe have shown that
heterochromatin formation is important for, or indicative
of, centromere inactivation. This also appears to be true
for centromere inactivation in plants. Recent work in
maize has shown distinct differences in DNA methyla-
tion patterns between active and inactive centromeres on
B chromosomes (Koo et al. 2011). Using a DNA fiber-
based technique, cytosine methylation was mapped with-
in highly repetitive DNA sequences, revealing that active
centromeres are hypomethylated, while inactive centro-
meres are hypermethylated. Active centromeres were
enriched for 5-methylcytosine (5mC) signals at the
ZmB satellite arrays but hypomethylated at the regions
containing CentC-CRM retrotransposons that were inter-
spersed between the satellite sequences. Conversely,
inactive centromeres had nearly uniform 5mC signals
throughout both the ZmB arrays and flanking regions,
creating an overall contiguously hypermethylated state.
The differential methylation of ZmB and CentC-CRM
blocks at active centromeres may favor loading and
propagation of CENH3 given that CENH3 nucleosomes
are associated with the CentC-CRM blocks and ZmB
repeats associate with canonical H3 nucleosomes (Jin et
al. 2005). Propagation of CENH3 nucleosomes may
prevent methylation of ZmB sequences at active B cen-
tromeres, maintaining their hypomethylation. Alterna-
tively, CENH3 could recruit demethylases to ZmB sites
during the cell cycle to establish an undermethylated
state. Consequently, during B-centromere inactivation,
loss of CENH3 may leave underlying CentC-CRM
sequences unprotected so that they can now become
heavily methylated.
Inactive plant centromeres, based on studies in maize,
lack CENH3, CENP-C, PH3S10, and are hypermethy-
lated (Fig. 2b). These modifications suggest that, like
inactive centromeres in fission yeast, inactive centromeres
in plants adopt a heterochromatic structure. Studies in
wheat have supported this conclusion. Wheat has been
utilized for centromere investigation since 1946 when
Sears first reported a transmissible dicentric wheat chro-
mosome that was found to contain one primary centro-
mere and a weaker secondary centromere (Sears and
Camara 1952). In contemporary studies that evaluated
CENH3 immunofluorescence and microtubule attach-
ment, this dicentric chromosomewas actually identified
as tricentric, with one large and two small centromeres
600 K.M. Stimpson et al.
(Zhang et al. 2010). This chromosome was often func-
tionally tricentric, but stable, presumably due to the dom-
inant pulling capacity of the large centromere during
meiotic anaphase. However, in those versions that did
not remain functionally tricentric, both of the small cen-
tromeres were inactivated. While there were no sequence
changes at the inactive centromeres, they were epigenet-
ically distinct from the active in that they appeared cyto-
logically to have higher levels of the heterochromatic
histone modifications H3K27me2 and H3K27me3. Col-
lectively, these studies in plants have revealed that inactive
centromeres exhibit many features of heterochromatin,
both at the level of DNA and chromatin.
Dicentrics in humans
The occurrence of dicentric chromosomes in humans has
been appreciated since the 1960s (De la Chapelle et al.
1966; Ockey et al. 1966). Many of these dicentrics were
associated with birth defects such as Turner Syndrome
and Down Syndrome and with reproductive abnormali-
ties. Although dicentrics can occur between any two
chromosomes, some types are more prevalent than others
in the human population. These include Robertsonian
translocations (ROBs) and isochromosome X [i(X)] (De
la Chapelle and Stenstrand 1974; Warburton et al. 1973).
ROBs involve any two of the ten acrocentric chromo-
somes (13, 14, 15, 21, and 22), although rob(13;14) and
rob(14;21), account for approximately 85 % of dicentric
ROBs ascertained from patients (Therman et al. 1989).
Early studies of patient-derived ROBs revealed that cen-
tromere inactivation occurred in the majority, particularly
in those that were inherited. The inactive centro-
meres were shown to lack CENP-A, CENP-C, and
CENP-E, and these features are shared by inactive cen-
tromeres of other non-ROB dicentric human chromo-
somes (Warburton et al. 1997; Sullivan and Schwartz
1995; Earnshaw and Migeon 1985;Fisheretal.1997;
Page et al. 1995a). In a series of patient-derived ROBs, it
was also observed that chromosome 14 remained active
most often, irrespective of the other acrocentric involved
in the ROB while the centromere of chromosome 15 was
more likely to be inactivated (Sullivan et al. 1994). These
results imply that some centromeres are strongeror less
amenable to centromere inactivation. However, studies of
both de novo ROBs and i(X)s have also revealed that that
some dicentric chromosomes remain functionally dicen-
tric (Lange et al. 2009;Higginsetal.1999; Sullivan and
Willard 1998). It was suggested that shorter inter-
centromeric distances promoted the retention of two
functional centromeres, similar to what had been ob-
served in budding yeast. It is presumed that steric con-
straints on dicentrics with small inter-centromeric distances
may reduce the possibility for improper microtubule
attachments or orientation of centromeres to opposite
spindle poles.
A limitation of studying patient-derived dicentrics
has been that most are evaluated months to decades
after the dicentric has formed. By this time, centro-
mere fate has been determined, established, and is
simply being maintained. Furthermore, the dicentrics
obtained from patient samples presumably represent
the most stable versions of dicentric chromosomes, so
that the spectrum of dicentric fates in humans may not
be fully appreciated. However, two studies of engi-
neered i(X)s and ROBs have been important in reveal-
ing dicentric behavior after formation. The first assay
involved creating dicentric isochromosomes of the
human X short arm [i(Xp)] in a rodent background
(Higgins et al. 1999). The dicentric i(Xp)s that were
produced exhibited a range of inter-centromeric dis-
tances, from a few megabases to over 20 Mb. These
studies revealed several classes/fates of dicentric
chromosomes, including (1) functionally monocentric
chromosomes, in which one of the two genetically
identical centromeres was inactivated; (2) functionally
dicentric chromosomes, in which both centromeres
remained active; and (3) dicentric chromosomes that
exhibited heterogeneous centromere activity (Higgins
et al. 2005). Serial single cell clones from this latter
class revealed that centromere activity was usually
clonal, but centromere state (i.e., functionally mono-
centric or dicentric) could switch within a population
of proliferating cells. Molecular analysis showed that
the size of the alpha satellite DNA at the centromeres
of these chromosomes did not change, suggesting that
inactivation occurred primarily due to epigenetic
changes. The i(Xp)s exhibited both short and large
inter-centromeric distances, but those with more dis-
tantly located centromeres could undergo centromere
inactivation or maintain two functional centromeres
suggesting that there was not an absolute correlation
with inter-centromeric distances and centromere fate.
In a more recent study, dicentric chromosomes were
produced in a human cell background by transiently
expressing a mutant version of telomere protein TRF2,
or dnTRF2 (Stimpson et al. 2010). The
Dicentric chromosome behavior 601
mutant protein behaves as a dominant-negative, binding
to endogenous TRF2 and displacing it from chromosome
ends, resulting in chromosome end-fusions (van Steensel
et al. 1998). Expression of dnTRF2 can be controlled by
doxycyline in the cell culture media, so that after its
expression is shut off, cells containing dicentrics contin-
ue to proliferate (Stimpson et al. 2010). Hundreds of
dicentrics were produced in this in vitro assay, and unex-
pectedly, the most were fusions between the human acro-
centric chromosomes (i.e., induced ROBs). The dicentrics
varied in structure so that inter-centromeric distances
could be studied in conjunction with the fates of the de
novo dicentric fusions. These studies revealed that ~50 %
of dicentrics maintain two active centromeres, even after
150 cell divisions. Even dicentrics with large (>20 Mbp)
inter-centromeric distances were stable through at least 20
cell divisions. The remaining dicentric fusions underwent
centromere inactivation between 4 days and 20 weeks
after formation. In about half of these induced dicentrics,
centromere inactivation was accompanied by the tempo-
rary appearance of small, marker-sized chromosome frag-
ments that were shown by immunostaining and FISH to
contain both CENPs and alpha satellite DNA homolo-
gous to the inactive centromere of the dicentric. Using
semi-quantitative FISH, it was observed that the alpha
satellite array of the inactive centromere became reduced
in size after centromere inactivation. These results sug-
gested that one mechanism of dicentric stabilization and
centromere inactivation in humans involves partial dele-
tion of the alpha satellite array (Fig. 2b). Since CENP-A
chromatin assembles on only a portion of the multi-
megabase alpha satellite arrays at endogenous human
centromeres (Sullivan et al. 2011), centromere inactiva-
tion could be explained by removal of the CENP-A
chromatin portion of the array. Indeed, decreases in
alpha satellite array size at inactivated centromeres have
been suggested from studies of patient-derived dicen-
trics (Fisher et al. 1997; Maraschio et al. 1990). In the
remainder of induced dicentric fusions with inactive
centromeres, there was no evidence of centromeric de-
letion, suggesting that similar to the engineered i(Xp)s,
epigenetic mechanisms are also involved in centromere
inactivation (Fig. 2b).
Concluding remarks and future challenges
It is clear from studies spanning the early days of
McClintocks work in maize to contemporary
experiments on engineered dicentrics in yeast and mam-
mals that dicentric behavior is complex and is associated
with multiple outcomes. In general, dicentrics are
unstable in most organisms, with the exception of
humans. But, irrespective of the organisms, those that
are retained experience similar fates. Dicentrics in bud-
ding and fission yeasts, plants, and mammals can be
stabilized by total or partial centromeric deletion. The
mechanisms could involve recombination, break-
induced replication, or non-homologous end joining,
since all of these processes have been associated with
centromeres (Pennaneach and Kolodner 2009;Pobiega
and Marcand 2010; Thrower et al. 2003). A notable
difference between centromeric deletion in yeast and
human dicentrics is that alpha satellite DNA, the ge-
nomic marker of the human centromere, is not com-
pletely removed during inactivation. Instead, only the
portion associated with CENP-A/CENH3, which pre-
sumably identifies the site of kinetochore assembly,
appears to be eliminated. Spatial and temporal incorpo-
ration of the centromeric H3 variant CENP-A/CENH3
maintains the location and function of the centromere.
Newly synthesized CENP-A/CENH3 is loaded into
chromatin in late telophase/early G1 by the escort pro-
tein HJURP (Dunleavy et al. 2009; Foltz et al. 2009).
Thus, removal of CENP-A/CENH3, and other centro-
mere/kinetochore proteins, from a centromere destined
for inactivation must occur, in addition to blocking the
loading of new CENP-A/CENH3. It is not known if
existing CENP-A/CENH3 nucleosomes, recruitment of
additional factors, or H3-containing nucleosomes within
centromeric chromatin guide incorporation of new
CENP-A/CENH3 or if such factors are recognized by
HJURP or intermediates. It would be consistent with
any of these models if centromere inactivation occurred
by simultaneously deleting existing CENP-A/CENH3
and nearby accessory chromatin that targets new CENP-
A/CENH3 deposition.
Studies of dicentrics in S. pombe,plants,and
humans also provide strong support for epigenetic
mechanisms of centromere inactivation that include
dramatic changes in the chromatin organization of
the inactive centromere. Inactive centromeres exhibit
markers of heterochromatin and lose euchromatic
modifications such as histone acetylation and
H3K4me2. The loss of euchromatic histone modifica-
tions such as H3K4me2 or H3K36me2 during centro-
mere inactivation makes sense in the context of how
centromeric chromatin is normally organized.
602 K.M. Stimpson et al.
H3K4me2 and H3K36me2 nucleosomes are present
within the CENP-A-containing region of the alpha
satellite array (Sullivan and Karpen 2004; Bergmann
et al. 2011). Removal of H3K4me2 and H3K36me2
may signify other changes at inactive centromeres,
such as a decrease in alpha satellite transcription.
Future experiments will be needed to determine if
changes in centromeric transcription are required for
or accompany inactivation.
Studies of dicentrics in plants and human ROBs have
suggested that the choice of which centromere is inacti-
vated may be nonrandom (Han et al. 2009; Sullivan et
al. 1994). This implies that there are differences in the
strengthof functional centromeres or in the ease of
inactivating certain centromeres. Mechanistically, this
phenomenon could be linked to genomic or epigenetic
features of individual centromeres, such as satellite array
size or chromatin composition. In plants, smaller cen-
tromeres are preferentially inactivated (Han et al. 2009).
The effect of alpha satellite array size on centromere
inactivation remains to be tested in humans. It is well
known that alpha satellite array size can vary by 10- to
20-fold among chromosomes, so it is possible that chro-
mosomes with consistently smaller arrays are more like-
ly to be inactivated. Still, other factors, such as sequence
characteristics, repeat monomer length, CENP-B box
density, nucleosome positioning, or DNA looping,
may equally influence the choiceof which centromere
is inactivated on a dicentric human chromosome.
An aspect of dicentric behavior that appears to be
unique to humans is the observation that dicentrics are
equally likely to exist as functionally dicentric, versus
functionally monocentric, chromosomes (Higgins et al.
1999; Sullivan and Willard 1998; Lange et al. 2010). In
patient-derived dicentrics (i.e., dicentric Xs and many de
novo ROBs) short inter-centromeric distances have been
proposed to influence centromere function, so that dicen-
trics with closely spaced centromeres are more likely to
remain functionally dicentric. However, over 80 % of
patient-derived ROBs undergo centromere inactivation
and even dicentric isochromosome Xs with closely
spaced centromeres experience centromere inactivation
(Page and Shaffer 1998; Sullivan and Schwartz 1995;
Sullivan et al. 1994). Data on engineered dicentric human
chromosomes argue that centromeric distance may not be
the strongest predictor of the functional state of a centro-
mere on a dicentric chromosome (Higgins et al. 2005;
Higgins et al. 1999;Stimpsonetal.2010). Centromere
inactivation might rely instead on chromosome-specific
features or may even occur differently in each cell. Dis-
secting the mechanism(s) of centromere inactivation is an
important, yet difficult, aspect of chromosome biology.
Other experimental systems to produce dicentric chromo-
somes will be important for defining the mechanisms of
genomic versus epigenetic centromere inactivation and
determining the underlying basis of centromere function.
Acknowledgments KMS was supported by NIH Ruth L.
Kirschstein National Research Service Award F31 AG034749
(NIA). BAS and research in the Sullivan lab are supported by
the National Institutes of Health grant R01 GM098500 (NIGMS)
and the March of Dimes Foundation (06-FY10-294). We apolo-
gize to our colleagues whose work on centromeres and dicentric
chromosomes could not be included due to space constraints.
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Dicentric chromosome behavior 605
    • "Under some conditions, if the same spindle pole is used for both centromeres, then this chromosome is successfully propagated to the progeny [48, 54, 55]. The second centromere on the chromosome can be also inactivated [48,[55][56][57][58]. To investigate whether cloned loci CEN1 and CEN2 have these centromeric properties, we integrated plasmids carrying these loci into the Y997 genome and analysed the karyotype of obtained integrants by PFGE. "
    [Show abstract] [Hide abstract] ABSTRACT: The wine and beer yeast Dekkera bruxellensis thrives in environments that are harsh and limiting, especially in concentrations with low oxygen and high ethanol. Its different strains' chromosomes greatly vary in number (karyotype). This study isolates two novel centromeric loci (CEN1 and CEN2), which support both the yeast's autonomous replication and the stable maintenance of plasmids. In the sequenced genome of the D. bruxellensis strain CBS 2499, CEN1 and CEN2 are each present in one copy. They differ from the known " point " CEN elements, and their biological activity is retained within ~900–1300 bp DNA segments. CEN1 and CEN2 have features of both " point " and " regional " centromeres: They contain conserved DNA elements, ARSs, short repeats, one tRNA gene, and transposon-like elements within less than 1 kb. Our discovery of a miniature inverted-repeat transposable element (MITE) next to CEN2 is the first report of such transposons in yeast. The transfor-mants carrying circular plasmids with cloned CEN1 and CEN2 undergo a phenotypic switch: They form fluffy colonies and produce three times more biofilm. The introduction of extra copies of CEN1 and CEN2 promotes both genome rearrangements and ploidy shifts, with these effects mediated by homologous recombination (between circular plasmid and genome centromere copy) or by chromosome breakage when integrated. Also, the proximity of the MITE-like transposon to CEN2 could translocate CEN2 within the genome or cause chromosomal breaks, so promoting genome dynamics. With extra copies of CEN1 and CEN2, the yeast's enhanced capacities to rearrange its genome and to change its gene expression could increase its abilities for exploiting new and demanding niches.
    Full-text · Article · Aug 2016
    • "The view that dicentric chromosomes are broken in mitosis and undergo breakage-fusion-bridge (BFB) cycles originates from McClintock's cytological observation of corn chromosomes (McClintock, 1938; McClintock, 1941). More recently, the fate of dicentric chromosomes has been studied in yeast as well as plants (reviewed in Stimpson et al., 2012). Here, we document the behavior of dicentric chromosomes in human cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve leads to frequent telomere fusions. The resulting dicentric chromosomes have been proposed to drive genome instability. Here, we examine the fate of dicentric human chromosomes in telomere crisis. We observed that dicentric chromosomes invariably persisted through mitosis and developed into 50–200 μm chromatin bridges connecting the daughter cells. Before their resolution at 3–20 hr after anaphase, the chromatin bridges induced nuclear envelope rupture in interphase, accumulated the cytoplasmic 3′ nuclease TREX1, and developed RPA-coated single stranded (ss) DNA. CRISPR knockouts showed that TREX1 contributed to the generation of the ssDNA and the resolution of the chromatin bridges. Post-crisis clones showed chromothripsis and kataegis, presumably resulting from DNA repair and APOBEC editing of the fragmented chromatin bridge DNA. We propose that chromothripsis in human cancer may arise through TREX1-mediated fragmentation of dicentric chromosomes formed in telomere crisis.
    Article · Dec 2015 · Frontiers in Plant Science
    • "There are even reports about tricentric (with three centromeres; Zhang et al., 2010) and meta-polycentric (with up to five centromeres) chromosomes (Neumann et al., 2012Neumann et al., , 2015). Typically, di-or tricentric chromosomes arise as a consequence of profound genome rearrangements (Stimpson et al., 2012) although naturally occurring di-and meta-polycentric chromosomes do exist. Stabilization of di-and tricentric chromosomes can occur via different mechanisms. "
    [Show abstract] [Hide abstract] ABSTRACT: The centromere, visible as the primary constriction of condensed metaphase chromosomes, is a defined chromosomal locus essential for genome stability. It mediates transient assembly of a multi-protein complex, the kinetochore, which enables interaction with spindle fibers and thus faithful segregation of the genetic information during nuclear divisions. Centromeric DNA varies in extent and sequence composition among organisms, but a common feature of almost all active eukaryotic centromeres is the presence of the centromeric histone H3 variant cenH3 (a.k.a. CENP-A). These typical centromere features apply to most studied species. However, a number of species display “atypical” centromeres, such as holocentromeres (centromere extension along almost the entire chromatid length) or neocentromeres (ectopic centromere activity). In this review, we provide an overview of different atypical centromere types found in plants including holocentromeres, de novo formed centromeres and terminal neocentromeres as well as di-, tri- and metapolycentromeres (more than one centromere per chromosomes). We discuss their specific and common features and compare them to centromere types found in other eukaryotic species. We also highlight new insights into centromere biology gained in plants with atypical centromeres such as distinct mechanisms to define a holocentromere, specific adaptations in species with holocentromeres during meiosis or various scenarios leading to neocentromere formation.
    Full-text · Article · Oct 2015
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