Polo-like kinase 1 (Plk1): an Unexpected Player in
Bing Song1,3, X Shawn Liu2,3and Xiaoqi Liu2,3*
Regulation of cell cycle progression is important for the maintenance of genome integrity, and Polo-like kinases
(Plks) have been identified as key regulators of this process. It is well established that Polo-like kinase 1 (Plk1) plays
critical roles in mitosis but little is known about its functions at other stages of the cell cycle. Here we summarize
the functions of Plk1 during DNA replication, focusing on the molecular events related to Origin Recognition
Complex (ORC), the complex that is essential for the initiation of DNA replication. Within the context of Plk1
phosphorylation of Orc2, we also emphasize regulation of Orc2 in different organisms. This review is intended to
provide some insight into how Plk1 coordinates DNA replication in S phase with chromosome segregation in
mitosis, and orchestrates the cell cycle as a whole.
Keywords: DNA replication, ORC2, phosphorylation, Plk1
1. The cell cycle and DNA replication
The cell cycle plays fundamental roles in many cellular
events, such as proliferation, survival and amplification.
Deregulation of the cell cycle might lead to abnormal cell
growth, which causes cancer or induces cell death
through apoptosis. The eukaryotic cell cycle comprises
four stages, G1, S, G2 and mitosis. One of the major
tasks throughout the cell cycle is to accurately transfer
genetic information from parental cells to the next gen-
eration. Thus, the two most important stages of the cell
cycle are S phase, in which DNA replication occurs, and
mitosis, in which the replicated chromosomes are equally
segregated into two daughter cells .
It is well accepted that DNA replication is initiated bi-
directionally at specific loci on chromatin, namely the ori-
gins of replication. However, how these origins are
selected is still not quite clear. The simplest and best
understanding of origins of replication is from study of the
budding yeast, Saccharomyces cerevisiae. In this organism,
replication origins are specified by the autonomous repli-
cation sequences (ARS), which are around 100 base pairs
and contain a shared 11-base-pair autonomous consensus
sequence (ACS). Origin Recognition Complex (ORC)
binds directly to ACS to initiate DNA replication. How-
ever, even in a simple system such as this, the ACS is not
sufficient in itself to predict the origin; the exact location
of ACS on the chromosome is also a critical element.
Active origins are usually located at intergenic regions,
which explains why only 400 out of 12,000 ACS sites are
functional in S. cerevisiae [2,3]. On the other hand, the ori-
gins of replication of the fission yeast Schizosaccharomyces
pombe differ from those of S. cerevisiae. First, the origins
are larger in S. Pombe, usually from 500 to 1000 base
pairs; second, the origins of fission yeast do not have an
ARS-like consensus sequence. However, evidence does
show that the origins of replication of S. Pombe are located
mostly at intergenic regions of high A-T content. ORCs
with the AT-hook domain preferentially bind to AT-rich
islands of DNA to initiate DNA replication [4-7]. The
situation is much more complicated in multicellular
organisms, as DNA replication can be initiated at any loca-
tion during early development of Xenopus laevis and
Drosophila melanogaster. But during later development
origins of replication are chosen from asymmetric AT-rich
regions under the specific influence of epigenetic factors
such as gene transcription, nucleosome position, etc.
[8-10]. A global search for origins of replication in mouse
and Chinese hamster cells revealed that CpG islands with
a high GC content but a low methylation level are usually
not only the sites for transcription but also for initiation of
* Correspondence: firstname.lastname@example.org
2Department of Biochemistry, Purdue University, West Lafayette, IN 47907,
Full list of author information is available at the end of the article
Song et al. Cell Division 2012, 7:3
© 2012 Song et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
DNA replication [11,12]. Origins are not all fired at the
same time, but instead are activated in early, mid or late
stages of S phase. Furthermore, not all origins are activated
during S phase. Instead, only a subset is activated during
undisturbed replication whereas others, the so-called “dor-
mant origins”, are activated in the case of DNA replication
stress such as DNA damage [13-15].
DNA replication starts with a series of sequential steps
from the formation of pre-replicative complex (pre-RC)
by ORC, which recognizes the origin of DNA replication
during G1 phase. ORC is a heterohexamer complex con-
tains six members, Orc1 to Orc6. They were originally
identified as ARS-binding proteins in S. cerevisiae ,
and named sequentially from Orc1 to Orc6 according to
their descending molecular weight. ORC homologue pro-
teins (mainly Orc1 to Orc5) were later identified in
almost all organisms including Homo sapiens [16-18]. All
ORCs can bind preferentially to asymmetric AT-rich
regions of DNA and function as the loading base for the
formation of the pre-RC complex. These proteins are
considered to be the only proteins that directly recognize
the origins of replication, however in budding yeast Noc3
protein may also be involved . Then cell division
cycle 6 (Cdc6) and helicase-loading protein Cdt1 are
recruited to the complex, followed by subsequent loading
of the minichromosome maintenance protein (MCM)
complex. The MCM complex is a heterohexamer that
contains six members (Mcm2-7), and has DNA helicase
activity, which will later unwind the DNA and allow bi-
directional movement of the replication fork. This activa-
tion process also involves many other DNA replication
factors such as CDC45, GINS complex, SLK2, Treslin,
GEMC1, MCM10, DBF4 and RPA. All these proteins
ensure proper loading of DNA polymerase and subse-
quent unwinding of DNA . The formation of pre-RC
and activation of the origin of replication have to be
tightly regulated to ensure that DNA replicates only once
per cell cycle. Once an origin has been activated at a spe-
cific locus, it will be inactivated so that re-activation at
the same locus will be inhibited within the same cell
cycle. During S phase, most Cdc6 proteins are phos-
phorylated by cyclinA-Cdk2 and exported to the cyto-
plasm for degradation, whereas a subset of Cdc6 proteins
remains bound to chromatin . Cdt1, a critical replica-
tion licensing factor, is also regulated by several mechan-
isms during S phase. Geminin, an inhibitor of Cdt1,
binds to and inhibits Cdt1 on chromatin [22,23]. In addi-
tion, Cdt1 is ubiquitinated and degraded by SCFskp2and
DDB1Cul4[24,25]. The MCM complex is phosphorylated
by Cdc7-Dbf4 and released from the template when
DNA replication is completed [26,27]. From G2 to M
phase, Cdc6 and the MCM complex are dephosphory-
lated. Geminin is ubiquitinated by APCcdc20so that Cdt1
is released from inhibition  and pre-RC can be
reformed to prepare for the next round of DNA
2. Protein phosphorylation and Regulation of
Orc2 in DNA replication
Protein phosphorylation is one of the most well-studied
post-translational modifications. It is a reaction catalyzed
by a kinase, whereby a phosphate group is added to a ser-
ine, threonine or tyrosine residue. The effect on the pro-
tein thus modified either enhancement or inhibition of
enzymatic activity, or interference with protein-protein
interaction, etc., influences various further biological
Since Orc2 is a major component of the DNA replica-
tion machinery, its regulation during DNA replication
has attracted much investigation. As early as 1999, it was
shown that cyclin A-CDK phosphorylates Orc2 in Xeno-
pus  and that this phosphorylation event inhibits
loading of Orc2 onto chromatin. Given the fact that
CDKs are the master regulators of the cell cycle, it is not
surprising that CDKs regulate DNA replication through
phosphorylation of Orc2. Fission yeast Cdc2 phosphory-
lates Orc2 at four CDK-consensus sites . This phos-
phorylation starts at S phase and peaks in G2/M to
prevent re-replication, thus ensuring that the genome
replicates only once per cell cycle. In S. cerevisiae, phos-
phorylation of Orc2 by CDK decreases chromatin loading
of Mcm proteins, in contrast, dephosphorylation of Orc2
promotes chromatin loading of Mcm proteins and initia-
tion of DNA replication . The expression level of
Orc2 protein is not cell cycle regulated, but studies do
show that the localization and association of specific pro-
teins associated with Orc2 change during cell cycle pro-
gression. In S. cerevisiae , Orc1-6 remain associated with
chromatin throughout the cell cycle as a complex
[32-35]. However, only Orc2-5 associate with chromatin
continuously in mammalian cells. Orc1 dynamically dis-
sociates from chromatin during S phase and re-associates
with it at late M/early G1 phase . Mammalian ORCs
exist as a variety of complexes including Orc1-6, Orc2-6,
or Orc2-5, but the exact role of the ORCs that remain on
chromatin after origin firing is still not understood. Stu-
dies from yeast and human cells indicate a possible invol-
vement of Orc2 in sister-chromatid cohesion and mitotic
chromosome condensation [37,38]. With the concept of
both dormant and active origins along replicating DNA,
it is also reasonable to speculate that Orc2 stays on chro-
matin to maintain a dormant origin to counteract DNA
replication stress, since it is a critical factor of pre-RC in
cases of depletion of other pre-RC components [39,40].
3. Plk1 and its role in mitosis
Polo kinase was first discovered in Drosophila melanogaster
where it had a knock-out phenotype of a mono-spindle
Song et al. Cell Division 2012, 7:3
Page 2 of 7
pole surrounded by chromosomes to form a circle .
The human Polo-like kinase 1 (Plk1) was cloned in 1994,
and its expression has been correlated with cell prolifera-
tion . Five mammalian Plks have been identified so far:
Plk1, Plk2, Plk3, Plk4 and Plk5 . Plk1 and its homolo-
gues in budding yeast (Cdc5), fission yeast (Plo1), Droso-
phila (Polo), nematodes (PLK-1) and Xenopus (Plx1) have
been extensively studied . All Plks share a similar
domain topology, a kinase domain on the amino-terminal
region and a polo-box domain (PBD) on the carboxyl-
terminal region. Recent advances with the development of
small molecule inhibitors have the advantage of inhibition
of Plk1 at post-prophase. The use of these inhibitors has
revealed roles of Plk1 in cell cycle regulation, mainly during
mitosis, including mitotic entry, centrosome maturation,
cohesin release, Golgi fragmentation, microtubule-kineto-
chore attachment, spindle elongation, and cytokinesis
[44,45]. Consistent with these functions, Plk1 localization is
also dynamic during cell cycle progression, moving from
centrosomes to spindle poles, kinetochores and midbodies
. The role of Plk1 during development has not as yet
been well studied in vivo since knockout of Plk1 in the
mouse causes embryonic lethality . During the G2/M
transition, Plk1 phosphorylates cyclinB-Cdk1, the key regu-
lator of mitotic entry, and Cdc25, which can dephosphory-
late inhibitory phosphorylations on Cdk, consequently
resulting in Cdk1 activation for mitotic entry . During
nuclear envelop break down (NEBD), Plk1 phosphorylates
p150glued, the largest subunit of the dynein/dynactin
motor complex, at centrosomes during late G2 phase and
promotes movement of p150gluedto the nuclear envelop.
Plk1 phosphorylation of p150gluedfacilitates the generation
of a deep nuclear envelop pocket or invagination to drive
NEBD . During mitotic progression, chromosomes
undergo dramatic morphological changes, and chromo-
some condensation and separation are the critical steps in
this process. Plk1 phosphorylation of Topoisomerase II-
alpha at Serine 1337 and Serine 1534 increases its decate-
nation activity, which is critical for sister-chromatid segre-
gation by decatenating the DNA duplexes . Plk1
phosphorylates several kinetochore proteins, such as
BubR1, Clip170 and PBIP1 to assist establishment of bipo-
lar spindles during metaphase [50-52]. Replicated sister
chromatids are held together by Cohesin. Plk1 phosphory-
lates one of the Cohesin subunits to promote separation of
two sister chromatids . Anaphase-promoting complex/
cyclosome (APC/C) is an E3 ubiquitin ligase important for
the metaphase to anaphase transition. Plk1 phosphoryla-
tion of EMI1, an APC/C inhibitor, leads to its degradation
and thus contributes to the activation of APC/C and subse-
quent metaphase to anaphase transition [54,55]. Plk1 also
controls the initiation of cytokinesis through direct interac-
tion with RacGAP50C to regulate the GTPase RhoA .
Under conditions of disturbed cell cycle progression, Plk1
has also been reported to regulate DNA-damage check-
point recovery by targeting G2-and S-phase-expressed 1
(GTSE-1), a p53 negative regulator. This phosphorylation
event leads to accumulation of GTSE-1 in the nucleus,
where it binds to p53, and subsequently shuttles it out of
the nucleus. p53 is degraded in the cytoplasm to inactivate
the checkpoint signal and to promote reinitiation of the
cell cycle  (Figure 1). Topors, which has both ubiquitin
and SUMO-1 E3 ligase activity towards p53, is also phos-
phorylated by Plk1; this enhances its ubiquitination activity
and inhibits its sumoylation activity toward p53, resulting
in p53 degradation .
4. Role of Plk1 in DNA replication
Since the major loss-of-function phenotype of Plk1 is
cell cycle arrest at mitosis, we know little about the
function of Plk1 in DNA replication, another important
stage during cell proliferation. Multiple studies have
indicated the involvement of polo kinase in DNA
A possible role of Cdc5, a mammalian Plk1 homologue,
at the origin of DNA replication complex in budding
yeast was reported as early as 1996 . It was shown
that Cdc5 phosphorylates DNA replication initiation pro-
tein Dbf4 in vitro , suggesting a possible role of Cdc5 in
DNA replication. Further studies also showed a synthetic
lethal phenotype of Cdc5 with Orc2 but not with other
replication factors, such as Dbf4, Cdc7 or Orc5, indicat-
ing that Cdc5 and Orc2 might perform related functions
during DNA replication in yeast. More interestingly, a
Cdc5 mutant has a loss of chromosome phenotype that
can be rescued by plasmids containing additional origins
of replication. Although mitotic arrest is the most
obvious phenotype of Plk1 depletion, long term Plk1
knockdown does lead to slow S-phase progression .
Several other publications also reported interactions
between Plk1 and replication factors, such as Mcm2,
Mcm3, Mcm7 and Orc2, suggesting involvement of Plk1
in DNA replication [61,62]. Yim and Erikson found that
depletion of Plk1 with lentivirus induced pre-RC forma-
tion defects and reduced DNA replication during subse-
quent S-phase progression . This result can be
partially explained by phosphorylation of histone acetyl-
transferase binding to the origin recognition complex 1
(Hbo1) by Plk1. Plk1 phosphorylation of Hbo1 at Ser57
regulates pre-RC loading of Mcm2 and Mcm6 proteins
 (Figure 2). Recent studies have shown that Polo
kinase is involved not only in undisturbed DNA replica-
tion but also in replication under stress conditions. Aphi-
dicolin treatment leads to stalled replication forks and
thus checkpoint activation with activated Chk1. Yoo and
colleagues showed that Xenopus Plx1 phosphorylates the
checkpoint mediator protein Claspin at Ser934 to pro-
mote dissociation of Claspin from chromatin and thus
Song et al. Cell Division 2012, 7:3
Page 3 of 7
Figure 1 Functions of Plk1 in mitosis. Plk1 functions are list below the corresponding mitotic stages. Plk1 substrates and interacting partners
are listed below the dashed line corresponding to Plk1 functions. Green: microtubules; blue: chromosomes; red: kinetochores. This listing only
focuses on topics covered in this review.
Figure 2 Functions of Plk1 in DNA replication. During undisturbed DNA replication, Plk1 phosphorylation of Hbo1 promotes Mcm complex
loading thus pre-RC formation. When DNA replication is under stress, checkpoint activation causes stalled replication fork. Plk1 phosphorylation
of Orc2 promotes the maintenance of pre-RC on dormant origins.
Song et al. Cell Division 2012, 7:3
Page 4 of 7
inactivation of Chk1. This step ensures that cells recover
from replication checkpoint-induced cell cycle arrest. In
support of this notion, cells with Claspin S934A mutant
do not adapt to the replication checkpoint even after
long interphase arrest . It has also been reported that
Plx1 can be recruited to chromatin by ATR-dependent
phosphorylation of Mcm2 at Ser92. This recruitment is
essential for proper DNA replication under stress condi-
tions such as aphidicolin treatment . However, the
mechanism of Plx1 as a critical component for DNA
replication under stress still needs further investigation.
Studies from other organisms also support the role of
Plk1 in DNA replication under stress. Avian FANCM
protein-deficient cells cannot restart stalled replication
forks but instead fire dormant origins to complete DNA
replication while the cells are under replication stress.
Inhibition of Plk1 by different chemical inhibitors blocks
DNA synthesis recovery in FANCM-deficient cells but
not FANCM-WT cells , suggesting a strong link
between Plk1 and dormant origin formation or firing
under replication stress. More significantly, we recently
found that Plk1 phosphorylates Orc2 at Ser188 and that
this phosphorylation event promotes DNA replication
under various stress conditions, such as low dose UV,
hydroxyurea, aphidicolin and thymidine treatments, in
different human cancer cell lines. To understand the
mechanism behind this intriguing observation, we
demonstrated that Orc2 phosphorylated at Ser188 by
Plk1 associates with DNA replication origins and that
cells expressing Orc2-S188A fail to maintain functional
pre-RC under DNA replication stress. We further
showed that the intra-S-phase checkpoint is activated in
Orc2-S188A-expressing cells to cause delay of S-phase
progression. Our study suggests a novel role of Plk1 in
maintenance of genomic integrity by promoting DNA
replication under conditions of stress  (Figure 2).
Ever since the discovery of Polo kinase and its knockdown
phenotype of cell cycle arrest at mitosis, studies have long
been focused on the roles of Polo kinases in different
aspects of mitosis. Although Plk1 is activated and peaks at
G2/M, its expression starts in early S phase with basal
level activity. Increased understanding of the role of Plk1
in DNA replication either under undisturbed or stressful
conditions reveals that Plk1 functions not only as a mitotic
kinase but also as a coordinator of DNA replication in S
phase and mitosis. Thus, Plk1 is a very important propeller
of cell cycle progression.
We appreciate Eleanor Erikson for critical reading of the paper. Support from
the Purdue University Center for Cancer Research Small Grants Program is
gratefully acknowledged. This work is also supported by National Science
Foundation (MCB-1049693), Elsa U. Pardee Foundation (204937), and Uniting
against Lung Cancer (09107892).
1Department of Biological Sciences, Purdue University, West Lafayette, IN
47907, USA.2Department of Biochemistry, Purdue University, West Lafayette,
IN 47907, USA.3Purdue Center for Cancer Research, Purdue University, West
Lafayette, IN 47907, USA.
BS and XSL drafted the manuscript. BS and XL critically edited and approved
The authors declare that they have no competing interests.
Received: 21 December 2011 Accepted: 6 February 2012
Published: 6 February 2012
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Song et al. Cell Division 2012, 7:3
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67. Schwab RA, Blackford AN, Niedzwiedz W: ATR activation and replication Download full-text
fork restart are defective in FANCM-deficient cells. EMBO J 2010,
Cite this article as: Song et al.: Polo-like kinase 1 (Plk1): an Unexpected
Player in DNA Replication. Cell Division 2012 7:3.
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