Cyclin-dependent advancement through G1 phase, with peak expression prior

kinases(CDKs) are master regulators of the eukaryotic cell cycle (Morgan DO.

The Cell Cycle: Principles of Control. London: New Science Press; 2007). They
are serine/threonine kinases consisting of the catalytic subunit, the CDK, and
a regulatory subunit, the cyclin, whose oscillatory protein levels drive the
periodic activation of CDKs. In the budding yeast Saccharomyces cerevisiae, 9
cyclins bind to a single CDK, cdc28, to confer substrate specificity either by
directly modulating its catalytic activity(Morgan 2005), or targeting it to a
specific subcellular location(Morgan 1997).The sequence variations give rise to
the different intrinsic properties of individual cyclin proteins, and
consequently different cyclins possess overlapping but distinct functional
capacities and are under differential regulations and restricted to different
subcellular locations. (Shuhui Lim, Philipp Kaldis 2013)(Gopinathan et
al., 2011)(Cross&Blooms2007). At
different windows of time in the cell cycle, different CDK substrates are
present and cellular environments differ. The activities of cyclin-cdk
complexes are therefore highly dependent on the cell-cycle stages and hence the
timing of expression and presence of cyclins at stable levels(Morgan 1997). As
a result, the activity of CDK is largely dependent on the substrate specficity
and specificity in time and space associated with individual cyclin-CDK
complexes which in turn depends on the presence of different cyclins. Cyclin
specificity- the ability of specific cyclins to target CDK to different
substrates- is the basis for the temporo-spatial control of CDK. Different
cyclins-cdc28 complexes act in combination to orchestrate the occurrence of
cell-cycle events in an ordered and irreversible fashion. In the budding yeast,
9 cyclins are involved in promoting the cell-cycle progression by regulating
the CDK catalytic activity with temporal and spatial specificity. G1-phase
cyclins- cln1, cln2, cln3- are required for the advancement through G1 phase,
with peak expression prior to START in G1. Mitotic B-type cyclins clb1, clb2,
clb3, clb4 are required for mitosis but inhibit the mitotic exit, whereas
early-expressed B type cyclins clb4 clb5 and clb6 drive S-phase
transition.  (Cross&Bloom 2007,
Bertoli 2013) To a large extent, the cyclin specificity is because of substrate
specificity, subcellular localizations, and differential regulations at the
level of transcription, inhibition and destruction(Cross&Bloom2007).  SUBSTRATE
significant overlap in cyclin functional capacities exists such that mitotic
Cdk1 activity can drive earlier cell cycle events as well as mitosis (Hu F,
2005), and a G1 cyclin expressed at high level is sufficient to drive DNA
replication and to promote later cell cycle phase specific transcription (Palou
R, 2015). Also, G1 cyclins especially cln1/2 have shown great similarity in the
sequences indicating the genetic redundancy and strains deleted for any two CLN
genes are still viable (BrendaAndrews&VivienMeasday, 1998) Still,
the differences in substrate specificity of cyclins are important in vivo,
contributing to a great extent to the ordering of cell cycle. For instance, the
specific Clb3–Cdk1 interaction with ?-tubulin Tub4 in-vivo identified using the
optimized cytosine deaminase protein-fragment complementation assay (OyCD PCA)
and further confirmed in in-vitro kinase assay has shown the unique role of
clb3 in regulating the mitotic spindle assembly during the formation of
interpolar microtubules (ip-MTs) and proves that clb3 contain elements that can
target cdc28 to specific substrate. (Ear, 2013)(Ear,2016) Also,
clb5 cannot block mitosis exit which is the normal function of clb2 (Jacobson, M. D., 2000) while
the replacement of clb5 with clb2 failed to efficiently phosphorylate protein
targets and delayed the onset of S phase (Morgan 2005). This difference in clb2
and clb5 might because clb5 have lower kinase activity towards the general
targets but have high affinity for a large group of highly specific
protein targets such as sld2 (required for initiation of replication)
(Masumoto, H. 2002) and cdh1(required for accumulation of cyclins and
other regulators) (Peters, J. M.  2002)
owing to its hydrophobic patch that can recognize RXL motif in the target
substrate (Morgan 2005). This specificity provides an replication control
switch. (2004 william gm) 

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Furthermore, B-type cyclin clb2,
though with strong kinase activity, cannot phosphorylate targets of G1 cyclins
efficiently. (Morgan 2005) This is because a Leu/Pro-rich LP motif is present
in the target substrates of G1 cyclins(such as transcriptional inhibitor whi2)
which preferentially interact with the substrate interaction interface on cln2.

and compensates for the weak cln2-cdc28 kinase activity. (Kõivomägi, 2011)
(Bhaduri 2011)This docking interface in cln2 allows muliti-site phosphorylation
of its substrates at the G1/S transition but not the later phase, promoting timely
cell cycle entry(Bhaduri 2015). This multisite phosphorylation might allow the
integration of signals to make a switch-like response (Kõivomägi, 2011)