Báo cáo khoa học: From meiosis to postmeiotic events: Alignment and recognition of homologous chromosomes in meiosis ppt

Meiotic recombination of homolo-gous chromosomes is important for ensuring the cor-rect segregation of chromosomes during the two rounds of nuclear division: reductional segregation of h

From meiosis to postmeiotic events: Alignment and

recognition of homologous chromosomes in meiosis

Da-Qiao Ding1, Tokuko Haraguchi1,2,3and Yasushi Hiraoka1,2,3

1 Kobe Advanced ICT Research Center, National Institute of Information and Communications Technology, Kobe, Japan

2 Graduate School of Frontier Biosciences, Osaka University, Suita, Japan

3 Department of Biology, Graduate School of Science, Osaka University, Toyonaka, Japan

Introduction

Meiosis is an essential process for sexually reproducing

eukaryotic organisms, producing haploid gametes or

spores from a diploid cell In this process, one round

of DNA replication is followed by two consecutive

nuclear divisions to halve the number of chromosomes

A characteristic feature of meiosis is the behavior

exhibited by homologous chromosomes Homologous

chromosomes form a pair and recombine with each

other in meiosis, whereas they behave independently in

mitotic cell cycles Meiotic recombination of

homolo-gous chromosomes is important for ensuring the

cor-rect segregation of chromosomes during the two

rounds of nuclear division: reductional segregation of

homologous chromosomes in the first division,

and equational segregation of sister chromatids in the

second division

The process of homologous recombination has been extensively studied at the molecular level (L Sze´kvo¨l-gyi and A Nicolas, this issue [1]), and mechanisms for DNA strand exchange have been determined at atomic resolution (W Kagawa and H Kurumizaka, this issue [2]) However, before a pair of homologous DNA strands can interact with each other, they must find each other within the cell nucleus How chromosomes can find their homologous partners to be paired has been a long-standing question [3–8] Considering the enormous size of the genome, it is unlikely that DNA sequences are directly compared over the entire gen-ome in the nucleus, like a nucleotide blast search of a database Instead, the process of homologous recogni-tion may involve chromosome-specific identifiers that can recognize homology at a first glance without

com-Keywords

bouquet arrangement; double-strand break;

homologous chromosome pairing; KASH

domain protein; meiosis; recombination;

SUN domain protein; synaptonemal

complex; telomere; transcription

Correspondence

Y Hiraoka, Graduate School of Frontier

Biosciences, Osaka University,

1-3 Yamadaoka, Suita, Japan

Fax: +81 6 6879 4622

Tel: +81 6 6879 4620

E-mail: hiraoka@fbs.osaka-u.ac.jp

(Received 10 August 2009, revised 21

October 2009, accepted 5 November 2009)

doi:10.1111/j.1742-4658.2009.07501.x

Recombination of homologous chromosomes is essential for correct reduc-tional segregation of homologous chromosomes, which characterizes meio-sis To accomplish homologous recombination, chromosomes must find their homologous partners and pair with them within the spatial con-straints of the nucleus Although various mechanisms have developed in different organisms, two major steps are involved in the process of pairing: first, alignment of homologous chromosomes to bring them close to each other for recognition; and second, recognition of the homologous partner

of each chromosome so that they can form an intimate pair Here, we dis-cuss the various mechanisms used for alignment and recognition of homol-ogous chromosomes in meiosis

Abbreviations

DSB, double-strand break; SC, synaptonemal complex; SPB, spindle-pole body.

paring nucleotide sequences in detail, e.g structural

fea-tures specific to each chromosome In fact, pairing of

homologous chromosomes involves several cytological

steps: spatial alignment of homologous chromosomes

accompanied by extensive intracellular rearrangement

of chromosomes, dramatic changes in chromosome

structures, recognition of homologous chromosomes,

recombination of homologous chromosomes, and

devel-opment of a structure called the synaptonemal complex

(SC), which intimately connects the homologous

chro-mosomes along their entire lengths [9] (Fig 1) Of these

steps, it is recognition for which the mechanisms remain

largely unknown Mechanisms dependent on or

inde-pendent of double-strand breaks (DSBs) of DNA have

both been found Here, we give an overview of the

cur-rent understanding of how homologous chromosomes

pair in meiosis We focus on the mechanisms used for

homologous alignment obtained from recent studies in

the fission yeast Schizosaccharomyces pombe and the

nematode Caenorhabditis elegans, and propose models

for homologous recognition

Alignment of homologous

chromosomes

Pairing of homologous chromosomes occurs at an

early stage of meiosis, involves searching for

homolo-gous partners, and leads to intimate connections along

the entire lengths of homologous chromosomes At

this stage of meiosis, a characteristic arrangement of

chromosomes called the ‘bouquet’ arrangement, in which chromosomes are bundled at the telomere to form a bouquet-like arrangement, is observed in a wide variety of organisms [3,4,10–12] (Fig 1C,D) To form a bouquet arrangement, telomeres are attached

to a restricted area of the nuclear envelope, generating

a polarized configuration of chromosomes (Fig 1B–D) These chromosomal events occur during meiotic pro-phase, while the nuclear envelope is intact

An extreme form of the bouquet arrangement has been observed in the fission yeast Schiz pombe, and the underlying molecular mechanisms have been exten-sively studied in this organism Schiz pombe cells nor-mally grow in the haploid state in the presence of sufficient nutrients; upon nitrogen starvation, haploid cells of the opposite mating type conjugate to form a diploid zygote In a zygote, two nuclei fuse together, and fusion of haploid nuclei is immediately followed

by characteristic movements of the elongated nucleus, called a ‘horsetail’ nucleus The horsetail nucleus moves back and forth between the cell ends for about

2 h After the nuclear movements cease, two rounds of nuclear division occur Thus, the horsetail period, cor-responding to meiotic prophase, provides the only opportunity for homologous chromosomes to pair and recombine with their homologous partners This situa-tion has made Schiz pombe an attractive experimental system, as we can investigate every event that occurs between homologous chromosomes during the horse-tail period of a few hours

Premeiotic interphase

Meiotic prophase

A

B

C

D

E

Fig 1 Pairing and recognition of homologous chromosomes Two pairs of homologous chromosomes are shown inside the nucleus, with the centrosome immediately outside the nucleus Each pair of homologous chromosomes is shown in magenta or green; dark and light lines

of the same color indicate homologous chromosomes Centromeres are indicated by closed circles (A–E) Putative chromosome identifiers are indicated by shaded circles (B, C) (A) During premeiotic interphase, unpaired homologous chromosomes are distributed within the nucleus (B) Putative chromosome identifiers are formed along each chromosome at the beginning of meiotic prophase (C, D) After chromo-somes are aligned by bouquet formation, putative chromosome identifiers recognize the homologous partner (E) A pair of homologous chro-mosomes are synapsed along their entire length at the end of meiotic prophase.

The Schiz pombe horsetail nuclear movements are

mediated by astral microtubules, which radiate from

the spindle-pole body (SPB; a microtubule-organizing

center in fungi), and a dynein protein motor [13,14]

The telomeres remain clustered at the leading edge of

the moving nucleus throughout the movements [13,15]

Observation of homologous pairing in living meiotic

cells has demonstrated that telomere clustering and

oscillatory chromosomal movements spatially align

homologous chromosomes in the early stages of

mei-otic prophase to promote their contact [16] In the

early stages, the arm regions of homologous

chromo-somes become close to each other independently of

recombination (in the absence of Rec12), and these

contacts are stabilized later in a

recombination-depen-dent (Rec12-depenrecombination-depen-dent) manner [16,17] Schiz pombe

Rec12 is a homolog of Saccharomyces cerevisiae

Spo11, which is required for DSB formation, and

therefore for recombination [18] At the centromere

regions, however, homologous associations gradually

increase during the horsetail stage, with similar

dynam-ics being observed in both wild-type and rec12 mutant

cells, suggesting that pairing at the centromere is

stabi-lized in a DSB-independent manner [16]

The ultimate form of pairing is synapsis, which, in

many organisms, is accomplished by the formation of

the SC, a tripartite structure connecting homologous

chromosomes (Fig 1E) It is known, however, that

some organisms do not develop SCs between paired

sets of homologous chromosomes, although they are

recombined Schiz pombe is an example of such

organ-isms lacking canonical SCs [19] In this organism,

interestingly, the continuous pulling movements of the

chromosomes may compensate for the lack of stable

synapsis between homologous chromosomes

Motions of chromosomes for their

alignment and pairing

The process of homologous chromosome pairing

requires mechanisms for finding homologous

chromo-somes and, at the same time, preventing non-specific

contacts between heterologous chromosomes During

this process, significant motions of chromosomes are

expected to occur within the nucleus It is generally

thought that clustering of telomeres, or the bouquet

formation, provides a way of promoting homologous

pairing by reducing the freedom of movement of

chro-mosomes within the nucleus Subsequently, oscillatory

movements of the entire nucleus occur in Schiz pombe

In some other organisms, intranuclear movements of

chromosomes are observed, e.g in the budding yeast

S cerevisiae [20–23] or in rat spermatocytes [24]

Either kind of chromosomal motion probably has dual roles: first, to act as an attractive force by agitating chromosomes to increase their chance of contact with

a homologous partner, and second to act as a repulsive force by disrupting contact between nonhomologous chromosomes Contacts between homologous chromo-somes would result in a stable, physical link, and the elimination of heterologous chromosomes, and, over time, homologous chromosomes would eventually pair along their entire lengths

Studies in Schiz pombe have also revealed a mecha-nism for the intranuclear motion of chromosomes [25,26] Members of conserved families of SUN and KASH domain proteins, Sad1 and Kms1, are involved

in the intranuclear chromosomal motions tethering telomeres to the SPB In general, SUN and KASH domain proteins form a complex that spans the nuclear envelope [27,28] The Sad1–Kms1 protein complex is localized exclusively at the SPB, but is transiently enriched at the telomeres on the nuclear envelope spe-cifically during the process of bouquet formation (telo-mere clustering) During this process, the Sad1–Kms1 protein complex interacts with telomeres on the nucleo-plasmic side, and with a dynein protein motor on the cytoplasmic side In this way, telomeres are moved by the driving force generated by the dynein motor on microtubules, which is transmitted by the Sad1–Kms1 protein complex across the nuclear envelope

An interesting mechanism for homologous pairing and recognition has been observed in the nematode

C elegans In this organism, special nontelomeric regions on chromosomes play a role analogous to telo-meres in bouquet arrangement, and act as a pairing center that promotes pairing and synapsis of the chro-mosomes [29,30] The pairing center on each chromo-some is bound by one of the four zinc finger proteins HIM-8, ZIM-1, ZIM-2, and ZIM-3, providing a mech-anism for homologous recognition to occur [31,32] These proteins then attach to the nuclear envelope, where they interact with the SUN and KASH domain proteins, SUN-1 and ZYG-12 [33] It has been demon-strated that the SUN–KASH protein complex plays a role in moving chromosomes along the nuclear enve-lope using cytoskeletal motor proteins [26,27] Thus, this mechanism exhibited by the SUN–KASH protein complex is analogous to formation of the bouquet arrangement in Schiz pombe Furthermore, recent studies have revealed that similar mechanisms are likely to be involved in intranuclear chromosomal movements in S cerevisiae [20,21,23,34] The SUN– KASH protein complex provides a general mechanism for moving chromosomes within the nucleus using cytoskeletal forces through the nuclear envelope

Recognition of homologous

chromosomes

Bouquet formation appears to be a common

mecha-nism for the alignment of chromosomes in many

organisms However, the question still remains as to

how chromosomes recognize their homologous

part-ners It has been proposed that the interactions

between homologous DNAs with DSBs and the

con-sequent recombination are involved in homology

searching in S cerevisiae [5] On the other hand,

homologous pairing is independent of recombination

in many organisms [5,6] After chromosomes have

been aligned, if each chromosome had a unique

pat-tern of blocks of specific molecular components

along its length, such a pattern would generate a

chromosome-specific barcode, which could act as a

chromosome identifier (Fig 1B,C) Such markers on

the chromosome could be recognized at first glance

without direct comparison of DNA sequences

Heterochromatin blocks could form such a

chromo-some-specific barcode, and so could transcription

machinery In meiosis in male Drosophila,

homolo-gous recombination does not occur [35] In this

organism, it is reported that strong pairing sites

cor-respond to highly transcribed rDNA loci and histone

genes [36] A previous model proposed roles for

transcription and for a specialized transcription

fac-tory in homologous chromosome recognition and

pairing [37,38] In this model, DNA regions that are

under active transcription are attached to a specific

transcription factory, in which transcriptional

machinery proteins are aggregated, and those DNA

regions that are not undergoing transcription

pro-trude from the factory and form a chromatin cloud;

therefore, a chromosome appears as a linear array of

many factories and clouds In meiosis, chromosomes

are aligned in the chromosome bouquet Because

aligned homologous chromosomes have the same

pattern of factories and clouds in parallel, a

chroma-tin cloud could also join the factory on its homolog

for transcription, and in this way homologous

chro-mosomes would be tethered temporally When many

of these temporal interactions occurred, two

homolo-gous chromosomes would be zipped up their entire

length (Fig 1C,D) This model provides a possible

mechanism for how transcription results in

recogni-tion and pairing of homologous chromosomes A

similar model, in which pairing can be achieved

through joining of allelic transcription units to the

same transcription center, has also been proposed

for polyploid plants [39]

Contribution of homologous recombination to pairing Formation of DSBs of DNA is essential for the subse-quent recombination of homologous chromosomes In meiosis, DSBs of DNA are deliberately generated and healed by recombination between homologous chro-mosomes On the other hand, pairing and synapsis of homologous chromosomes can be achieved through DSB-dependent or DSB-independent mechanisms DSB-dependent pairing has been best investigated in the budding yeast S cerevisiae, and has also been found in animals and plants In meiosis, DNA DSBs are generated by a type II topoisomerase-like specialized enzyme, Spo11 Spo11 is then removed by the MRX (Mre11–Rad50–Xrs2) complex, and the 5¢-ends of DNA breaks are resected to expose 3¢-single-strand tails; a RecA-type recombinase, Rad51, then binds to the ssDNA and plays a role in searching for DNA that shares sequence homology [5,40] In S cerevisiae, about

2100 DSB hot spots have been mapped throughout the genome [41] It has been proposed that the interactions between homologous DNAs involved in the process of homology searching and recombination along the chro-mosomes allow DSB-dependent pairing to occur [5] However, even in a mutant lacking Spo11 and other key factors for DSB formation and recombination of DNA, some residual levels of pairing still remain, suggesting that a DSB-independent pairing mechanism may also be operating in this organism [42–44]

On the other hand, typical DSB-independent pairing

is found in Drosophila and C elegans In these organ-isms, initiation of pairing and synapsis of homologous chromosomes does not depend on DSB formation and recombination, but on the presence of some special chromosomal regions, although the mechanisms are different In Drosophila males, sex chromosomes pair and segregate without recombination or formation of SCs A 240 bp repeated sequence within the intergenic spacers of the rRNA genes acts as a cis-acting X–Y pairing site, and is responsible for faithful segregation

of X–Y chromosomes [36] In C elegans, DSBs are not required for homologous pairing [45], and instead a set

of four zinc finger proteins, each specifically binding with one or two pairing centers, are essential for pair-ing and synapsis, as described above In addition, it has been demonstrated that centromere heterochroma-tin plays a role in mediaheterochroma-ting DSB-independent pairing

in organisms such as Drosophila [46], C elegans [45], and Schiz pombe [16]

Contribution of homologous recombination to pair-ing may vary among species, dependpair-ing on the size

and number of chromosomes, the volume of the

nucleus, or the time allowed for pairing Physical

models based on computational simulation provide

predictions for contributions of such parameters to

the efficiency of homologous chromosome pairing

[47–49]

Perspectives

Although formation of the bouquet arrangement

reduces the spatial distance between homologous

chromosomes, which could promote the pairing

pro-cess, it does not directly drive recognition of

homol-ogous chromosomes How chromosomes identify

their homologous partners remains to be elucidated

The diversity of the underlying mechanisms present

in different organisms further increases the

complex-ity of this problem [5,6] In C elegans,

chromosome-specific recognition proteins are linked to cytoskeletal

motor proteins to tether homologous chromosomes

In Schiz pombe, we recently uncovered a novel

phe-nomenon relating noncoding RNA to homologous

chromosome pairing (D.-Q Ding, unpublished

results), implying that transcribed RNA mediates

rec-ognition of the respective DNA regions of

homolo-gous chromosomes This idea may be supported by

the finding that meiotic recombination hotspots

coin-cide with loci that express noncoding RNA in

Schiz pombe [50] It is tempting to speculate that

particular molecular patterns along each chromosome

provide a chromosomal barcode for the recognition

of homologous chromosomes

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