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Sister-chromatid cohesion is essential for proper chromosome segregation and faithful transmission

of the genome during the cell cycle (Morales and Losada, 2018; Uhlmann, 2016). Failure to estab-

lish or resolve cohesion in a timely manner leads to genomic instability and aneuploidy. Sister-chro-

matid cohesion is mediated by cohesin, a ring-shaped ATPase machine that consists of SMC1A,

SMC3, RAD21, and either STAG1 or STAG2 in human somatic cells (Haarhuis et al., 2014;

Losada and Hirano, 2005; Nasmyth and Haering, 2009; Onn et al., 2008; Peters et al., 2008;

Zheng and Yu, 2015). Cohesin rings topologically entrap DNA to generate physical linkages

beteen sister chromatids and enable cohesion. Cohesin regulates other chromosome-based pro-

cesses, such as DNA repair, transcription, and chromosome folding (Merkenschlager and Odom,

2013; Wu and Yu, 2012). These other functions of cohesin likely also involve the topological entrap-

ment of chromosomes or possibly the extrusion of DNA loops (Barrington et al., 2017;

Davidson et al., 2016; Haarhuis et al., 2017).

Cohesin is loaded onto chromosomes in telophase and G1 by the SCC2/4 plex (NIPBL/MAU2

in humans)(Ciosk et al., 2000; Gillespie and Hirano, 2004; Takahashi et al., 2004; Tonkin et al.,

2004; Watrin et al., 2006). Before DNA replication, the chromosome-bound cohesin is dynamic and

is actively removed from chromosomes by the cohesin-releasing factor WAPL ith the help of thescaffolding protein PDS5A or PDS5B (Chan et al., 2012; Kueng et al., 2006; Lopez-Serra et al.,

2013; Ouyang and Yu, 2017; Ouyang et al., 2013; Ouyang et al., 2016). During DNA replication

in S phase, a pool of cohesin is converted to the cohesive form, hich stably associates ith chromo-

somes and mediates sister-chromatid cohesion (Gerlich et al., 2006; Kueng et al., 2006). In human

cells, cohesion establishment requires the acetylation of SMC3 by the acetyltransferases ESCO1 and

ESCO2 and subsequent recruitment of sororin, hich antagonizes WAPL to stabilize cohesin on

chromosomes (Alomer et al., 2017; Hou and Zou, 2005; Nishiyama et al., 2010; Ouyang et al.,

2016; Rankin et al., 2005; Rolef Ben-Shahar et al., 2008; Roland et al., 2009; Unal et al., 2008;

Zhang et al., 2008a).

The checkpoint kinase proteins Mec1 and Rad53 are required in

the budding yeast, Saccharomyces cerevisiae, to maintain cell

viability in the presence of drugs causing damage to DNA or

arrest of DNA replication forks1±3. It is thought that they act by

inhibiting cell cycle progression, alloing time for DNA repair to

take place. Mec1 and Rad53 also slo S phase progression in

response to DNA alkylation4, although the mechanism for this

and its relative importance in protecting cells from DNA damage

have not been determined .Here e sho that the DNA-alkylating

agent methyl methanesulphonate (MMS) profoundly reduces the

rate of DNA replication fork progression; hoever, this moderation

does not require Rad53 or Mec1. The accelerated S phase in

checkpoint mutants4, therefore, is primarily a consequence of

inappropriate initiation events5±7.Wild-type cells ultimately plete

DNA replication in the presence of MMS. In contrast,

replication forks in checkpoint mutants collapse irreversibly at

high rates. Moreover, the cytotoxicity of MMS in checkpoint

mutants occurs speci?cally hen cells are alloed to enter S

phase ith DNA damage. Thus, preventing damage-induced

DNA replication fork catastrophe seems to be a primary mechanism

by hich checkpoints preserve viability in the face of DNA

To ensure that a plete set of the eukaryotic genome is

precisely duplicated during the limited period of S phase in

every cell cycle, DNA replication initiates at a number of

replication origins on chromosomes (Gilbert, 2001; Bell and

Dutta, 2002). As each chromosome region replicates in a

specific period ithin S phase, timing of origin activation

must be regulated. Although e have a groing understanding

of protein factors involved in initiation and elongation of

replication, the mechanisms of origin activation at the chromosome

level are yet to be clarified in detail. Thus, it is

important to determine locations of all replication origins on

chromosomes. Hoever, only small numbers of replication

origins have so far been identified in most organisms other

than budding yeast Saccharomyces cerevisiae (MacAlpine and

Bell, 2005).

The process of initiation of replication at individual replication

origins is posed of to major steps, licensing of

replication origins in G1 phase and activation of the origins in

S phase. In G1 phase, pre-replicative plexes (pre-RCs) are

formed at replication origins (Bell and Dutta, 2002; Kearsey

and Cotterill, 2003). This requires binding of the origin

recognition plex (ORC) to a replication origin, folloed

by assembly of the minichromosome maintenance (MCM)

plex, depending on the loading factors, Cdc6/Cdc18 and

Cdt1 (Diffley et al, 1994; Bell and Dutta, 2002). Although pre-

RC formation is essential for initiation of replication, it is not

in itself sufficient. Origin activation in S phase is regulated by

to conserved protein kinases, cyclin-dependent protein

kinase (CDK) and Cdc7–Dbf4 protein kinase (Dbf4-dependent

kinase, DDK). These kinases are required for assembly of

several other protein factors, including Cdc45 and GINS onto

pre-RCs. This may lead to activation of MCM helicase and

origin DNA uninding, and the replication machinery is

established through assembly of RPA and DNA polymerases

onto the single-stranded DNA (Bell and Dutta, 2002).

Although proteins involved in initiation of replication are

conserved among eukaryotes, the nucleotide sequences of

replication origins are very diverse among organisms

(Gilbert, 2001), mainly because of differences in DNA-binding

properties of ORCs. In budding yeast, ORC recognizes the

specific sequence called the ARS consensus sequence (ACS).

In contrast, no clear consensus sequence has been found in

origins in fission yeast, Schizosaccharomyces pombe (Clyne

and Kelly, 1995; Dubey et al, 1996; Okuno et al, 1999),

although AT-rich sequences to hich ORC preferentially

binds are required (Chuang and Kelly, 1999). Requirements

for specific sequences bee less clear in multicellular

organisms such as metazoans, and ORC exhibits little sequence

specificity in DNA binding in vitro (Vashee et al, 2003;

Remus et al, 2004). Therefore, it is important to determine the

locations of ORC binding and DNA synthesis experimentally.

Genome-ide analyses of replication kinetics and distribution

of ORC and MCM proteins using DNA microarrays have

Received: 24 July 2006; accepted: 8 January 2007; published online:

15 February 2007

*Corresponding author. Department of Biology, Graduate School of

Science, Osaka University, 1-1, Machikaneyama-cho, Toyonaka, Osaka

560-0043, Japan. Tel.:t81 6 6850 5432; Fax:t81 6 6850 5440;

E-mail: [email protected]

5Present address: The Scripps Research Institute, North Torrey

Pines Road, La Jolla, CA , USA

6Present address: Department of Biological Chemistry and Molecular

Pharmacology, Harvard Medical School, 240 Longood Avenue,

Boston, MA 02115, USA

The EMBO Journal (2007) 26, 1327–1339 |& 2007 European Molecular Biology Organization | All Rights Reserved 0261-4189/07

.embojournal.org

EMBO

JOURNAL

THE

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(本章完)

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