Directory UMM :Data Elmu:jurnal:P:PlantScience:Plant Science_BioMedNet:041-060:

reviews
The development of plants, compared with that of animals, is influenced much more by the environment in
which they grow, suggesting that plants have evolved
mechanisms that relay environmental signals to control cell division and ultimately plant growth. Most of
the divisional activity in plants is localized in small
groups of cells, called meristems (see Box 1), that are already present in the embryo and are active during most
of the life cycle of the plant. How environmental cues
trigger changes in cell-division activity in meristems –
that is, how the plant connects environmental
changes with molecular changes in the machinery
controlling the cell cycle – is largely unknown.
The cell cycle consists of the alternating phases of
DNA replication (S phase) and chromosome separation (mitosis, or M phase) interrupted by gaps
known as G1 (interval between M and S phases) and
G2 (interval between S and M phases). Important
controls operate at the transition points as cells
move from G1 into S phase, and from G2 into M
phase, primarily through the regulated kinase activity of cyclin-dependent kinases (CDKs).
Both the G1–S and G2–M phase transitions can be
controlled in plant cells in response to changing
conditions. For example, during the early stages of

root nodule initiation in pea and alfalfa, the root
cortical cells susceptible to Rhizobium infection are
in G0/G1 (Ref. 1). By contrast, before germination of
seeds, the cells of the embryo are arrested in G1, or
partly in G1 and partly in G2, depending on the
species2. An example of G2 control is found in
radish lateral root primordia, which are derived
from pericycle cells arrested in G2. These cells move
into M phase upon auxin stimulation3 and then
continue to proliferate, producing a lateral root primordium that eventually emerges from the side of
the primary root.
In addition to these specific developmental controls, the cell cycle in plants plays an important role
in growth responses to the environment. If the grass
Dactylis is exposed to increased levels of CO2, cells
in the shoot meristem increase their rate of proliferation, resulting in faster growth. This occurs partly
through an increase in the number of cells actively
involved in division, and partly through a shortening of the cell cycle, particularly the G1 phase4.
Interestingly, both the shoot and root apical meristems are a mosaic of fast and slow cycling cells, and
the main difference between these two populations
is in the length of G1 (Refs 5 and 6), suggesting that

this phase is the most responsive to signals that
change cell-cycle length. The significance of G1
controls in commitment to the cell cycle has been
shown in yeast, flies and mammals7, and, as excellent reviews covering the complete plant cell cycle
have appeared recently8–10, we will limit ourselves
here to a discussion of the G1–S transition in plants
and how this is controlled. At the end of the review,
we turn to the intriguing question of how cell division patterns are coordinated within the meristem.
The cyclin D–retinoblastoma–E2F pathway
Eukaryotic cells in G1 phase have several options.
The most obvious is that, in the presence of sufficient
trends in CELL BIOLOGY (Vol. 10) June 2000

Triggering the cell
cycle in plants
Bart G. W. den Boer and
James A. H. Murray
In essence, the mitotic cell cycle in eukaryotes involves the
duplication and separation of chromosomes, coupled to the
process of dividing one cell into two. Cytokinesis is therefore the

culmination of a series of events that were triggered during G1
phase, and brings the daughter cells back to the starting position
in G1 for another possible round of division. In all eukaryotes,
progression through the cell cycle is controlled by cyclindependent kinases that bind to positive regulators called cyclins.
This review explores some of the pathways that trigger the plant
cell cycle, with emphasis on the G1 phase. Examples include
signalling pathways involving glutathione and cellular redox
potential, the possible existence of a G1 DNA-damage
checkpoint, and the plant hormones auxin and cytokinin.
Progress in understanding the link between cell proliferation, cell
differentiation and the cell-cycle machinery in a developmental
context is discussed.

stimuli, they commit to further cell division and
progress into S phase with the initiation of DNA
synthesis. However, there are several other cell fates,
including differentiation, programmed cell death
and the adoption of a quiescent state (G0) (Fig. 1).
We will first summarize the molecular events associated with the first option, the G1–S transition, and
emphasize the important parallels found between

mammals and plants.
In mammalian cells, the retinoblastoma protein
(Rb) and its relatives, p107/p130, are important in
preventing cells from progressing into S phase, by
binding members of the E2F family of transcription
factors that are present on promoters driving
S-phase specific genes. Recently, it has been recognized that the active recruitment of histone
deacetylase by pRb is important in keeping E2Fresponsive genes switched off during G1, by creating
an inactive chromatin structure11. It is only when Rb
itself gets inactivated by phosphorylation in late G1
that genes under E2F control are relieved from repression and their subsequent expression can provide
the activities needed for S-phase entry12.
Phosphorylation of Rb in G1 is a two-step process
involving the sequential action of cyclin D–CDK

0962-8924/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0962-8924(00)01765-7

Bart den Boer is at
Aventis

CropScience N.V.,
Jozef Plateaustraat
22, B-9000, Gent,
Belgium; and
James Murray is at
the Institute of
Biotechnology,
University of
Cambridge,
Tennis Court
Road, Cambridge,
UK CB2 1QT.
E-mails:
bart.denboer@
aventis.com;
j.murray@
biotech.cam.ac.uk

245

reviews
G0
Programmed
cell death

CDK4 and CDK6 (the CDK partners of D-type cyclins), whereas members of the CIP/KIP family act
more broadly by inhibiting the kinase activity associated with cyclin D-, E- and A-dependent kinases15.

Plants
In plants, homologues of most of the key players
in the Rb pathway (Fig. 2) have been identified, and
Differentiate
most show structural and functional similarities to
their animal counterparts. As yeasts do not contain
direct homologues of proteins involved in the Rb
De-differentiate
pathway, the backbone of this pathway appears to
G1
G1
be conserved between animals and plants, but not

’stem cell’
fungi16,17. There are three main classes of plant
trends in Cell Biology
D-type cyclin (CycD) genes18, but these are not related to the individual groups of mammalian D-type
FIGURE 1
cyclins, indicating that the increase in gene number
Options for G1 cells in plants. Newborn G1 cells can start another round of division
in the cyclin-D family might have occurred inde(‘stem cell’) or exit the cycle (non-cycling cells). These cells die (programmed cell
pendently in animals and plants. As in animal cells,
death), return into the cell cycle or differentiate. In contrast to animals, differentiated
the transcription of some types of CycD is inducible
plant cells can more readily de-differentiate and re-enter the cell cycle,
during cell-cycle entry by mitogens, but generally
given the appropriate signals.
stays relatively constant once cells are involved in
continuous proliferation19.
13
and cyclin E–CDK complexes . It is initiated folLike animals, plants contain several types of CDKlowing stimulation by mitogens, which induce and
like genes, including direct homologues of fission
maintain D-type cyclin expression. This is followed

yeast cdc2+, which contains a consensus amino acid
by a wave of cyclin E expression in late G1 (Ref. 14).
sequence PSTAIRE in its cyclin-binding region.
The activities of these cyclin–CDK complexes is in
Direct homologues of cdc2 are called CDK1 or cdc2
turn constrained by CDK inhibitor proteins (CKIs).
in mammals, and cdc2a or CDK-a in plants. Plants
In mammals, these proteins fall into two families
have no direct equivalents of other mammalian
based on their structure and CDK targets. The INK4
CDKs, but have plant-specific CDK variants with the
family specifically inhibits the catalytic subunits of
consensus sequence PPTALRE (CDK-b1) or PPTTLRE
(CDK-b2). These are unique among
CDKs in showing cell-cycle regulation
ABA
ICK1
of expression, being transcribed only
Auxin
from S until M phase9. Differences are

seen in the expression timing of the
cycD3
Cytokinin
PPTALRE and PPTTLRE subgroups10.
CDK-a
Sucrose
cycD2
ICK1
In mammalian cells, the archetypal
Rb
PSTAIRE-containing CDK1 is involved
E2F inactive
mainly in the G2–M transition and alE2F
cycD
ternative CDKs control the G1 phase
P
cycD
S-phase genes (CDK4, CDK6) and the G1–S transition
CDK-a P
P

P
(CDK2). However, in plants, only CDK-a
CDK-a
Rb
protein (the CDK1 equivalent) has been
P
P
P ?
detected during the G1 phase. CDK-a,
CAK
however, is presumably not specific for
E2F E2F active
the G1–S transition as its levels are relatively constant during the cell cycle, and
S-phase genes
CDK-a-associated activity peaks at both
G1/S transition
START
the G1–S and the G2–M boundaries. Its
activity is supplemented by CDK-b kiG1
S

nase activity during G2–M. CycD cyclins
are regulatory partners of plant CDK-a
during the G1–S phase transitions.
trends in Cell Biology
What is the substrate for the cyclin
FIGURE 2 D–CDK activity? In mammals, Rb is the
preferred substrate of G1 kinases, and
Model for G1–S transition in plants. Cytokinin- and sucrose-induced D-type cyclins bind to cyclinRb-like homologues have been reported
dependent kinase-a (CDK-a) to form inactive heterodimers. Regulation of kinase activity after binding
in maize17 and tobacco20. In tobacco,
the cyclin might occur either by an inhibitor (ICK1) or by phosphorylation by an activating kinase
complexes of CDK-a with CycD3 can be
(CAK). Phosphorylation of the retinoblastoma protein Rb by CDK-a complexes releases the
detected in vivo, and, when expressed in
transcription factor E2F, which is the active molecule required to enter S phase. The phosphorylation
insect cells, these can phosphorylate the
of plant CDK-a by CAK and the presence of Rb–E2F complexes on the promoters of S-phase genes
tobacco Rb-related protein in vitro20.
have not been shown to occur in plants but are based on the mammalian G1–S model.

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Having established that the upstream components of the cyclin D–Rb pathway are conserved in
plants and animals, the next obvious question is
whether conservation continues downstream: in
other words, are there E2F transcription factors in
plants? Until recently, the only evidence was indirect, as it was shown that maize Rb1 can bind to
human and Drosophila E2F and inhibits the transcriptional activation ability of human E2F16. This
changed with the identification and analysis of
wheat and tobacco clones21,22. Wheat and tobacco
E2F were shown to interact respectively with maize
Rb1 and tobacco Rb in yeast two-hybrid assays. For
wheat E2F, the interaction was also confirmed
in vitro and the Rb-binding motif was mapped to the
C-terminal end.
CDK activity requires activating phosphorylation
by CDK-activating kinase (CAK)23, but there is little
evidence that this regulates cell-cycle progression.
However, inhibitory phosphorylation by wee1-like
kinases is likely to play a significant regulatory
role24. In addition, four CDK inhibitor (CKI) protein
genes are reported in plants, but only one, ICK1, has
been characterized biochemically25,26. ICK1 interacts with both CDK-a (cdc2a) and cyclin CycD3
in vitro, is an inhibitor of plant cdc2-like kinases and
its C-terminal consensus sequence resembles part of
the CDK2-binding domain of the mammalian CKI
p27Kip1 (Ref. 25). Its activity throughout the cell
cycle has not been investigated, nor is it clear
whether overexpression in plant cells can inhibit
progression. Interestingly, ICK1 expression is induced by the stress hormone abscisic acid, although
it is not known whether this is a direct effect25.
Thus, although several players involved in the
G1–S transition in plants are structurally and functionally similar to their animal counterparts, differences are apparent. For example, a cyclin E homologue has not been identified in plants. This might
not come as a surprise as cyclin E and the D-type cyclins bind to different CDKs (CDK2 and CDK4/6 respectively) in animals, and only one CDK activity
has been reported at the G1–S transition in plants9.
Perhaps plant Rb could be phosphorylated by sequential cyclin D kinase activity as there are three
main groups of plant CycD proteins with differential
regulation and timing of expression (CycD1–3)18.

DNA
damage

rml1/cad2
ABA

PARP
Auxin

Cytokinin

GSH

X

ICK1
cycD3/CDK-a

Y
?

G1

FIGURE 3
Potential signalling pathways feeding into the G1–S transition in plants. Genome
instability transcriptionally activates poly(ADP-ribose) polymerase (PARP). In
mammalian systems X = p53 and Y = p21, but their homologues have not been
identified in plants. The rml1/cad2 gene encodes the first enzyme of glutathione
(GSH) biosynthesis. When the intracellular GSH concentration falls below a threshold
level, the G1–S transition is blocked in dividing root cells. Depletion of auxin arrests
cells in G1, and abscisic acid (ABA) induces the inhibitor ICK1 transcriptionally. ICK1
can interact with both cycD3 and CDK-a (cdc2a). Cytokinin activates cycD3
transcription, and constitutive cycD3 expression can rescue the cytokinin
requirement of callus.

Pathways triggering the cell cycle in plants
The rest of this review focuses on four examples of
signalling pathways that feed into the plant cell
cycle (Fig. 3). The DNA damage and glutathione
pathways are not specific to plants, whereas the
study of pathways relating to auxin–cytokinin and
meristem function are plant-specific solutions to
the problems of integrating cell division with differentiation and development.

tumour suppressor protein p53 (Ref. 28) that activates transcription of p21CIP1, resulting in elevated
levels of this CKI. This inhibits the activity of G1
CDKs, leading to a G1 arrest29. The p53 protein can
associate with poly(ADP-ribose) polymerase (PARP),
another protein that senses DNA damage, and inhibition of PARP activity leads to loss of p21 upregulation in response to DNA damage30. PARP is catalytically activated by DNA strand breaks, and is
responsible for the poly(ADP-ribosylation) of various nuclear proteins using NAD as substrate31.
Although there is evidence that major DNA repair
mechanisms found in other species also occur in
plants32, it is not known whether a G1 checkpoint
control exists in plants. However, it is interesting to
note that one of the Arabidopsis PARP genes is transcriptionally activated by the genome instability resulting from a mutation in the DNA ligase I gene33,
suggesting that at least part of the DNA damage signalling pathway might be conserved. However, with
over 85% of the Arabidopsis genome sequence already completed, no proteins homologous to p53
have been found. As p53 is also intimately involved
in the control of apoptosis in animals34,35, its possible absence in plants raises the possibility of different links between the cell cycle, DNA damage
responses and programmed cell death36.

DNA damage pathway
DNA damage occurs in all living things and our
understanding of the control of cell cycle by DNA
damage has made enormous progress in yeasts and
mammals27. Mammalian cells are known to arrest in
G1 upon DNA damage. This block is induced by the

GSH-dependent control of the G1–S transition
Glutathione (GSH) is an abundant and ubiquitous
thiol with proposed functions in the adaptation of
plants to extreme temperatures, tolerance to xenobiotics and to biotic and abiotic environmental
stresses37. Until recently, a direct link between GSH

trends in CELL BIOLOGY (Vol. 10) June 2000

S
trends in Cell Biology

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(a)

(b)

Arabidopsis quiescent cells to enter the
cell cycle, as was shown in maize for
L1
ascorbic acid, another molecule involved in the removal of active oxygen
L2
P1
species40. Thus intracellular redox
P0
homeostasis could affect cell-cycle progression by regulating key components
of the G1–S transition37. It is not clear,
however, how this would operate at the
trends in Cell Biology
molecular level.
Oxidative stress and GSH-dependent
FIGURE 4 transduction pathways probably also
impinge on the animal cell cycle as
Cell proliferation in the shoot apex. (a) Scanning electron micrograph of a tobacco shoot apical
GSH depletion leads to an arrest of
meristem (SAM). Leaf primordia are initiated on the flanks of the apical meristem. P0 is the youngest
primordium, P1 the next oldest primordium, and P2 the oldest. Hatched line indicates the plane of
cell-cycle progression in human cells41.
section in (b). Bar, 100 mm. (b) Cross-section through the SAM and flanking leaf primordia. Note the
A candidate G1–S cell-cycle factor
layered configuration of the dome (L1 and L2). Proliferating cells in the peripheral zone are displaced
through which the GSH pathway might
towards the leaf primordia where eventually they will exit the cell cycle and differentiate. Black arrows
have its effect in mammals could be
indicate the direction of cell displacement. Bar, 100 mm.
the inhibitor p21, as mammalian cells
blocked in G1 due to a low GSH level
levels and the cell-division cycle was lacking, but this
show high levels of p21 protein41.
changed when Vernoux and colleagues uncovered a
role for intracellular GSH in the G1–S transition in
Auxin and cytokinin action
plants38 during the cloning of the ROOTMERISTEMIn higher plants, only two groups of hormones,
the auxins and cytokinins, are generally stimulatory
LESS (RML) gene. RML encodes the first enzyme of
to the proliferation of most cell types42. Many plant
GSH biosynthesis (g-glutamylcysteine synthetase).
Moreover, depletion of intracellular GSH by addition
tissues, such as leaf, root or stem pieces, can be exof an inhibitor of GSH biosynthesis to Arabidopsis or
planted into culture, where dedifferentiation and
tobacco seedlings or tobacco BY-2 cells abolishes cell
proliferation occur to form a callus of largely undivision. Interestingly, the cell-division block in
differentiated cells. This process normally occurs if
seedlings affects only the root meristem, and the
both
auxin
and
cytokinin
are
present.
shoot apical meristem is unaffected.
Conceptually, the link between auxin–cytokinin acIs there a physiological significance to the block of
tion and cell division has been around for more
cell division caused when intracellular GSH concenthan 40 years43, but the progress in understanding
tration is reduced artificially? In other words, does
the molecular basis of their action in cell proliferthe plant modulate its endogenous GSH levels duration has been very slow until recently. Auxin alone
ing normal development to change the cell-division
increases the level of a CDK protein in cultured tocycle? An indication that this could be the case is
bacco cells and stem pith explants, but addition of
that, in Arabidopsis roots, high levels of GSH (measa cytokinin was required for activation of this kiured by a reporter) are associated with proliferating
nase44. The b-glucuronidase reporter gene under
cells such as epidermal and cortical initials, whereas
control of the Arabidopsis CDK-a (cdc2a) promoter is
reduced levels of GSH were found in the slowly cyinducible by auxins and, to a lesser degree, by cycling cells of the quiescent centre that have an extokinins45. However, it is often difficult to separate
tended G1 (Ref. 39). It would be interesting to see
the direct control of cell-cycle genes by hormones
whether an increase in GSH levels could stimulate
from their indirect induction as a consequence of
the cell-cycle progress that the hormones provoke.
Progress in analysing modes of action has also been
BOX 1 – GLOSSARY
hampered by the different types of interaction that
both hormones show, depending on the plant
Primordium – A group of cells that will develop into a
species or tissue type46.
new organ.
At what point of the cell cycle do auxins and
cytokinins act? Somewhat confusingly, both horMeristem – group of cells acting as a source of cells for
mones have been associated with progression
all main plant organs.
through the G1–S and the G2–M control points.
Suspension cells arrest in both G1 and G2 phases
Pericycle – layer between the endodermis and the conafter they are transferred to medium containing
ducting tissue, from which lateral roots arise.
cytokinin but lacking auxin44,47. However, most
progress has been made in linking cytokinin to the
Cortex – bulk tissue in stem and root that lies between
cell cycle. First, cells of certain suspension cultures
the epidermis and the central tissues.
arrest in G2 when deprived of cytokinin, and these
cells have inactive CDK complexes. Addition of
Quiescent centre – small group of cells at the centre of
cytokinin or tyrosine dephosphorylation restores
the root meristem that rarely divides.
kinase activity47, suggesting that cytokinin-depleted
cells accumulate CDK–cyclin complexes that are
P2

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inactive due to phosphorylation of the threonine 14
and/or tyrosine 15 regulatory residues of the CDK
subunit. Second, in tobacco BY-2 cells, the cytokinin
biosynthesis inhibitor lovastatin is able to block
cells in G2, and this can be reversed by addition of
exogenous cytokinin48. However, proof that cytokinin operates through CDK dephosphorylation
in vivo is still lacking.
Evidence has emerged that cytokinin also regulates the G1–S transition. Cytokinin application to
shoot meristems reduces the size of chromosomal
DNA replication units, resulting in the closer spacing of sites of DNA replication initiation. This leads
to faster DNA synthesis, thereby providing a mechanism for the shortening of S phase that was observed49. More recently, CycD3 has been shown to
be induced by cytokinin in both cultured cells and
intact plants50, suggesting a role in the cytokinin
control of cell division. If CycD3 is a primary target
of cytokinin action in G1–S control, constitutive expression of this cyclin should be able to bypass the
requirement for cytokinin. In a key experiment,
CycD3 was expressed in stable Arabidopsis transformants, and was found to remove the requirement
for exogenous cytokinin during callus initiation and
growth from leaf pieces50. The timing of CycD3 induction occurs slightly before the expression of an
S-phase marker gene histone H4 in partially synchronized Arabidopsis cells, pointing to its action
during the G1 phase50. It is attractive to speculate
that the increase in the number of DNA replication
origins caused by cytokinin application might also
be due to increased CycD3-associated kinase activity. The different steps in the signalling pathway
from cytokinin to CycD3 are unknown but might
involve a phosphorelay as used in bacterial twocomponent signalling51 as CycD3 induction was
found to be independent of protein synthesis50.
Coordination of cell division in intact plants
Understanding plant growth and development requires an understanding of how plant cells grow and
divide and how positional information is integrated
with cell division. As meristems provide the cells
that eventually give rise to the root, leaves, stem and
flowers, it is essential to understand the molecular
controls underlying cell division in the primary root
meristems and shoot apical meristems52. Here we
take the divisional activity of cells present in the
shoot apical meristem (SAM) as an example (Fig. 4a).
SAMs of higher plants are not homogeneous, as
there is a gradient of cell division and growth rate
within the apex53. At the summit (central zone) cells
have long cell-cycle times, whereas displaced cells
that end up at the flank in emerging primordia divide faster. This reduction in cell-cycle time is due
mainly to a shortening of G1 phase, although the
G2 phase is reduced in some species5. This picture of
divisional activity is superimposed on the layered
structure of the SAM. Cells in the two outermost layers
(L1 and L2, Fig. 4b) divide primarily with cell walls
normal to the surface of the meristem, so cells in
these sheets rarely move from one layer to
another54. It is not known how the pattern of cell
trends in CELL BIOLOGY (Vol. 10) June 2000

division activity, which seems to bear no resemblance to the layered structure of the apex, is coordinated in these different layers, particularly
because there are cells with faster and slower cellcycle times in all meristem zones.
A little later, when groups of cells develop into organs, individual cells exit the cell cycle and differentiate into specific cell types. During maize leaf development, the exit from G1 occurs from tip to base,
and is correlated with Rb expression and loss of celldivision activity16.
Somehow, the fate of cells that are in G1, and
therefore could exit the cell cycle, is influenced by
signalling molecules originating from neighbouring
cells or cells even further away55. Little is known
about the connections between signalling pathways
operating at cell-type level in organs and the celldivision cycle, although several mutations have been
identified that disrupt patterned cell division operating in meristems, and some of the affected genes have
been cloned. This should allow the identification of
molecular pathways describing the connection
between known signalling cascades and the cell-cycle
machinery, – that is, the activity of cyclin–CDK
complexes. One might have expected to identify
cell-cycle components such as cyclins or CDKs by
this route, but this was not the case. Most of the
mutations are present in genes that encode
homeodomain proteins, components of a common
signal-transduction pathway or evolutionary conserved members of the piwi family56,57. Such genes act
upstream in cell division control, in the sense that they
are probably involved both in the correct patterning of
cell division within the meristem and in ensuring the
continued proliferation of meristem cells.
Recent work on the AINTEGUMENTA (ANT ) gene
suggests that it might exert a more direct regulation
on the proliferation of meristem cells as overexpression of ANT results in larger organs containing
more cells without changes to the morphology of
the final organ58,59. Conversely, a loss-of-function
ant mutation decreases floral meristem size and
floral organ size by reducing cell number59.
Conclusions and prospects
Yeasts, plants and mammals control progression
through their cell cycles by using CDKs that bind to
cyclins. During evolution, plants and mammals
have evolved into multicellular organisms with
many different cell types, a change that is marked by
the appearance of the cyclin D–Rb–E2F pathway.
Perhaps this is important in allowing the differentiation of multiple cell types in complex tissues.
Plants and animals have elaborated their cell-cycle
controls with kingdom-specific changes that allow
indeterminate development in plants, characterized
by the continuous production of new organs, on the
one hand, and the determinate development of animals, on the other. As plants are sessile, environmental changes can have profound effects on their
growth, which are likely to be reflected in the signalling pathways that connect to the cell cycle and
possibly in the details of the cell-cycle machinery
itself. The role of cytokinin is the first example where

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the molecular details of a plant hormone in
cell-cycle control are starting to be understood, and
the importance of oxidative stress is apparent from
the cell-cycle arrest brought about by inhibition of
glutathione biosynthesis. With the complete
genome sequence of Arabidopsis within reach, a
complete inventory of the cell-cycle genes in a
higher multicellular eukaryote is conceivable.
References

Acknowledgements
We thank Mike
May for providing
data prior to
publication and
Marc De Block for
drawing our
attention to PARP.
We apologize to
those whose work
was not
mentioned owing
to space
constraints.

250

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trends in CELL BIOLOGY (Vol. 10) June 2000