Cdc6

protein
Name = Cdc6


width = 125
caption =Crystal Structure of CDC6p from Pyrobaculum aerophilum.
Symbol = Cdc6
AltSymbols = YJL194W
EntrezGene = 853244
UniProt = P09119

Cdc6 is a protein in the budding yeast "Saccharomyces cerevisiae". Its name stands for "cell division cycle 6 protein" (Cdc6p) and it is an essential regulator of DNA replication in eukaryotic cells andplays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate S phase and mitosis. It is part of the pre-replicative complex (pre-RC) and is required for loading Minichromosome Maintenance (MCM) proteins onto the DNA, an essential step in the initiation of DNA synthesis.In addition, it’s a member of the family of AAA+ ATPases and highly associated toOrc1p.

Function

[
cite journal
author=Borlado LR, Méndez J
title=CDC6: from DNA replication to cell cycle checkpoints and oncogenesis
journal=Carcinogenesis
volume=29
issue=2
pages=237–43
year=2008
month=February
pmid=18048387
doi=10.1093/carcin/bgm268
url=http://carcin.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18048387] ] Cdc6p is an ATP binding protein and a member of the pre-replicative complex (pre-RC) together withthe origin-recognition complex (ORC), Cdt1 and the MCM complex (containing MCM2-7p). Cdc6passembles after ORC in an ATP dependent manner and is required for loading MCM proteins onto theDNA. Reconstruction of electron microscope images showed that the ORC-Cdc6p complex forms aring-shaped structure with similar dimensions to those of ring-shaped MCM helicase. [cite journal
author=Speck C, Chen Z, Li H, Stillman B
title=ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA
journal=Nat. Struct. Mol. Biol.
volume=12
issue=11
pages=965–71
year=2005
month=November
pmid=16228006
doi=10.1038/nsmb1002
url=http://dx.doi.org/10.1038/nsmb1002] It is thought that the Cdc6p-Cdt1 complex uses ATP hydrolysis to thread DNA through the central hole of the MCM doughnut. [Pollard, T.D., et al. (2008). Cell Biology. 2nd edition, p. 766-767] Mutations in the binding motif of Cdc6p strongly suggest that ATP binding and hydrolysis is essential for its function.cite journal
author=Bell SP, Dutta A
title=DNA replication in eukaryotic cells
journal=Annu. Rev. Biochem.
volume=71
issue=
pages=333–74
year=2002
pmid=12045100
doi=10.1146/annurev.biochem.71.110601.135425
url=http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.biochem.71.110601.135425?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov] The minimal requirement for DNA binding has been mapped within its 47-amino acid sequence.cite journal
author=Feng L, Wang B, Driscoll B, Jong A
title=Identification and characterization of Saccharomyces cerevisiae Cdc6 DNA-binding properties
journal=Mol. Biol. Cell
volume=11
issue=5
pages=1673–85
year=2000
month=May
pmid=10793143
pmc=14875
doi=
url=http://www.molbiolcell.org/cgi/pmidlookup?view=long&pmid=10793143] Furthermore Cdc6 indirectly inhibits activation of the p34cdc2/CDC28 M phase kinase, thus nuclear division is suppressed.cite journal
author=Bueno A, Russell P
title=Dual functions of CDC6: a yeast protein required for DNA replication also inhibits nuclear division
journal=EMBO J.
volume=11
issue=6
pages=2167–76
year=1992
month=June
pmid=1600944
pmc=556684
doi=
url=]

Regulation

Cdc6p is normally present at high levels during the G1 phase of the cell cycle. This is partly because theCDC6 gene is only transcribed during G1 phase. On the onset of the S phase, Cdc6p gets phosphorylated bythe Cdc28-Clb5-Clb6 complex (Cdk1) and consequently becoming inactivated. This has been shown by introducing mutations in Cdc6p at the consensus sites for Cdk1 phosphorylation (near the N-terminus) which inhibit degradation. Thephosphorylation can furthermore be catalyzed by Cdc28-Cln. The inactivated Cdc6p is then targeted fordegradation by SCFCDC4-dependent ubiquitinylation and afterwards degraded by the proteosome.Thus, the regulation of Cdc6p is tightly correlated to the activity of Cdk1 and since Cdk1-activityis oscillating once per cell cycle, the accumulation and degradation of Cdc6p alsooscillates.

Two states can be distinguished. In the first state (during G1 phase) Cdk1-activity is low, Cdc6p canaccumulate, hence the pre-RC can be formed but not activated. In the second state Cdk1-activity is high, Cdc6pbecomes inactivated, hence the pre-RC is activated but not formed. This change assures that DNA replication is performed only once per cell cycle. It has been shown that overexpression of Cdc6p doesnot induce re-replication in cognate cells, probably due to inhibition through CDK that resets the cellcycle clock to G1. Nevertheless it has been suggested that regulation of Cdc6p is one of several redundantmechanisms that prevent re-replication of the DNA in eukaryotic cells.cite journal
author=Drury LS, Perkins G, Diffley JF
title=The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast
journal=EMBO J.
volume=16
issue=19
pages=5966–76
year=1997
month=October
pmid=9312054
pmc=1170227
doi=10.1093/emboj/16.19.5966
url=http://dx.doi.org/10.1093/emboj/16.19.5966]

tructure

The crystallographic structure of a Cdc6p/Orc1-related protein from Pyrobaculum aerophilum (see Pyrobaculum) has been solved and three structural domains have been identified. Domain I and II form the ATP binding/hydrolysis site and are similar Similar to other AAA+ ATPases. Domain III is structurally related to awinged-helix domain, thus may interact with origin DNA. From studies with E. coli γ clamp loadingcomplex, it was suggested that domain III mediates protein-protein interactions with other AAA+ATPases in the pre-RC, thus suggesting that the Cdc6p builds a homodimer in its native form. The domains Iand II form a cashew-shaped molecule that bind ATP in the cleft and additionally build the sensor motiffor ATP/ADP recognition. These domains are also thought to mediate subsequent conformationalchanges. Nevertheless, the exact functional roles of these domains remain unclear.

Disease

It has been shown Cdc6p shows proto-oncogenic activity. Cdc6 overexpression interferes with theexpression of INK4/ARF tumor suppressor genes through a mechanism involving the epigeneticmodification of chromatin at the INK4/ARF locus. In addition, Cdc6p overexpression in primary cellsmay promote DNA hyperreplication and induce a senescence response similar to that caused byoncogene activation. These findings indicate that deregulation of CDC6 expression in human cells posesa serious risk of carcinogenesis. Down-regulation of CDC6 in prostate cancer was observed andassociated with phenotypic characteristics of aggressive prostate cancer.cite journal
author=Robles LD, Frost AR, Davila M, Hutson AD, Grizzle WE, Chakrabarti R
title=Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer
journal=J. Biol. Chem.
volume=277
issue=28
pages=25431–8
year=2002
month=July
pmid=12006585
doi=10.1074/jbc.M201199200
url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12006585] Furthermore it has beenobserved that Cdc6 is greatly up-regulated in cervical cancer, lung cancer and brain cancer.cite journal
author=Lau E, Tsuji T, Guo L, Lu SH, Jiang W
title=The role of pre-replicative complex (pre-RC) components in oncogenesis
journal=FASEB J.
volume=21
issue=14
pages=3786–94
year=2007
month=December
pmid=17690155
doi=10.1096/fj.07-8900rev
url=http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=17690155]

ee also

*Cdc6 homolog in humans

References

Weblinks

* [http://db.yeastgenome.org/cgi-bin/locus.pl?locus=YJL194W Cdc6 in the yeastgenome database]