Geminin: Difference between revisions

Jump to navigation Jump to search
m (Robot: Automated text replacement (-{{WikiDoc Cardiology Network Infobox}} +, -<references /> +{{reflist|2}}, -{{reflist}} +{{reflist|2}}))
 
imported>DferDaisy
(→‎Model organisms: ref tidy up)
 
(One intermediate revision by one other user not shown)
Line 1: Line 1:
<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Geminin, DNA replication inhibitor''', also known as '''GMNN''', is a [[protein]] in humans encoded by the ''GMNN'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GMNN geminin, DNA replication inhibitor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51053| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
Geminin is a nuclear protein that is present in most eukaryotics and highly conserved across species. Numerous functions have been elucidated for Geminin including roles in metazoan cell cycle, cellular proliferation, cell lineage commitment, and neural differentiation.<ref name="Kroll Review 2007">{{cite journal | vauthors = Kroll KL | title = Geminin in embryonic development: coordinating transcription and the cell cycle during differentiation | journal = Front. Biosci. | volume = 12 | issue = 4 | pages = 1395–409 | year = 2007 | pmid = 17127390 | pmc =  | doi = 10.2741/2156 }}</ref>
{{GNF_Protein_box
| image = PBB_Protein_GMNN_image.jpg
| image_source = [[Protein Data Bank|PDB]] rendering based on 1t6f.
| PDB = {{PDB2|1t6f}}, {{PDB2|1uii}}
| Name = Geminin, DNA replication inhibitor
| HGNCid = 17493
| Symbol = GMNN
| AltSymbols =; Gem; RP3-369A17.3
| OMIM = 602842
| ECnumber = 
| Homologene = 9292
| MGIid = 1927344
| GeneAtlas_image1 = PBB_GE_GMNN_218350_s_at_tn.png
| Function = {{GNF_GO|id=GO:0005515 |text = protein binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0008156 |text = negative regulation of DNA replication}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0045786 |text = negative regulation of progression through cell cycle}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 51053
    | Hs_Ensembl = ENSG00000112312
    | Hs_RefseqProtein = NP_056979
    | Hs_RefseqmRNA = NM_015895
    | Hs_GenLoc_db =   
    | Hs_GenLoc_chr = 6
    | Hs_GenLoc_start = 24883138
    | Hs_GenLoc_end = 24894306
    | Hs_Uniprot = O75496
    | Mm_EntrezGene = 57441
    | Mm_Ensembl = ENSMUSG00000006715
    | Mm_RefseqmRNA = NM_020567
    | Mm_RefseqProtein = NP_065592
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 13
    | Mm_GenLoc_start = 24759311
    | Mm_GenLoc_end = 24769328
    | Mm_Uniprot = Q5SZV9
  }}
}}
{{Orphan|date=September 2006}}  


'''Geminin, DNA replication inhibitor''', also known as '''GMNN''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GMNN geminin, DNA replication inhibitor| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51053| accessdate = }}</ref>
== History ==
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text =
}}
'''Geminin''' is a protein with a dual role during [[eukaryotic]] cell cycle.
'''Geminin''' was originally identified as a DNA replication inhibitor. Notwithstanding, recent experimental works show that Geminin can also promote DNA replication.


----
Geminin was originally identified as an inhibitor of [[DNA replication]] and substrate of the [[anaphase promoting complex]] (APC).<ref name="pmid9635433" /> Coincidentally, geminin was also shown to expand the [[neural plate]] in the developing [[Xenopus]] embryo.<ref name="pmid9671596">{{cite journal | vauthors = Kroll KL, Salic AN, Evans LM, Kirschner MW | title = Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation | journal = Development | volume = 125 | issue = 16 | pages = 3247–58 | year = 1998 | pmid = 9671596 | doi =  }}</ref>


'''Geminin''' has two roles in two different phases of the cell cycle::
== Structure ==


During S phase of the cell cycle '''Geminin''' is a negative regulator of DNA replication. Inhibition of '''Geminin''' during this phase (by [[RNAi]]) results in an extra round of replication of portions of the genome.
Geminin is a nuclear protein made up of about 200 amino acids, with a molecular weight of approximately 25 kDa.<ref name="pmid9635433">{{cite journal | vauthors = McGarry TJ, Kirschner MW | title = Geminin, an inhibitor of DNA replication, is degraded during mitosis | journal = Cell | volume = 93 | issue = 6 | pages = 1043–1053 | year = 1998 | pmid = 9635433 | doi = 10.1016/S0092-8674(00)81209-X }}</ref> It contains an atypical leucine-zipper coiled-coil domain. It has no known enzymatic activity nor DNA binding motifs.


During M phase of the cell cycle ([[mitosis]]) '''Geminin''' stabilizes the replication factor Cdt1 promoting DNA replication during the following cell cycle. In fact, inhibition of '''Geminin''' during mitosis (by RNAi) leads to destabilization of Cdt1 protein and impairment of DNA replication during the following cell cycle.
== Function ==


'''Geminin''' therefore ensures that one and only one round of replication occurs during each cell cycle.
=== Cell cycle control ===


Recently, '''Geminin''' has been found to be overexpressed in several malignancies and cancer cell lines. This supports the notion that '''Geminin''' has also a positive role in DNA replication and cell cycle progression.
Geminin is absent during [[G1 phase|G<sub>1</sub> phase]] and accumulates through [[S phase|S]], [[G2 phase|G<sub>2</sub> phase]] and [[mitosis|M phases]] of the cell cycle. Geminin levels drop at the [[metaphase]] / [[anaphase]] transition of [[mitosis]] when it is degraded by the [[Anaphase Promoting Complex]] (APC/C).<ref name="pmid9635433" />


----
==== S phase ====


'''Geminin''' is a nuclear protein. The protein consists of about 200 residues.  
During [[S phase]], geminin is a negative regulator of [[DNA replication]]. In many cancer cell lines, inhibition of geminin  by [[RNA interference|RNAi]] results in re-replication of portions of the genome, which leads to [[aneuploidy]].  In these cell lines, geminin knockdown leads to markedly slowed growth and [[apoptosis]] within several days.<ref name="pmid19487297">{{cite journal | vauthors = Zhu W, Depamphilis ML | title = Selective killing of cancer cells by suppression of geminin activity | journal = Cancer Res. | volume = 69 | issue = 11 | pages = 4870–4877 | year = 2009 | pmid = 19487297 | pmc = 2749580 | doi = 10.1158/0008-5472.CAN-08-4559 }}</ref>  However, the same is not true for primary and immortalized human cell lines, where other mechanisms exists to prevent [[DNA re-replication]].<ref name="pmid19487297"/>  Since geminin knockdown leads to cell death in many cancer cell lines but not primary cell lines, it has been proposed as a potential therapeutic target for cancer treatment.<ref name="pmid19487297"/>


'''Geminin''' is absent during G1 phase and accumulates through S, G2 and M phases of the cell cycle. '''Geminin''' levels drop at the metaphase/anaphase transition of [[mitosis]].
==== Mitosis ====


==References==
At the start of the S-phase until late mitosis, geminin inhibits the replication factor [[DNA replication factor CDT1|Cdt1]], preventing the assembly of the pre-replicative complex. In early G1, the APC/C complex triggers its destruction through ubiquitination. Although inhibition of geminin by RNAi leads to impairment of DNA replication during the following cell cycle in many cancer cell lines, no such cell cycle defect is seen in primary and immortalized cell lines (although Cdt1 levels are still reduced in these cells).<ref name="pmid19487297"/>
{{reflist|2}}
 
==Further reading==
Geminin therefore is an important player in ensuring that one and only one round of replication occurs during each cell cycle.
{{refbegin | 2}}
 
{{PBB_Further_reading
=== Developmental control ===
| citations =  
 
*{{cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi= }}
Geminin promotes early neural fate commitment by hyperacetylating the chromatin.<ref>{{cite journal | vauthors = Yellajoshyula D, Patterson ES, Elitt MS, Kroll KL | title = Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 108 | issue = 8 | pages = 3294–9 | year = 2011 | pmid = 21300881 | pmc = 3044367 | doi = 10.1073/pnas.1012053108 }}</ref> This effect allows neural genes to be accessible for transcription, promoting the expression of these genes. Ultimately, geminin allows cells uncommitted to any particular lineage to acquire neural characteristics.
*{{cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi= }}
 
*{{cite journal  | author=McGarry TJ, Kirschner MW |title=Geminin, an inhibitor of DNA replication, is degraded during mitosis. |journal=Cell |volume=93 |issue= 6 |pages= 1043-53 |year= 1998 |pmid= 9635433 |doi=  }}
Geminin has also been shown to interact with the [[SWI/SNF]] chromatin remodeling complex.<ref>{{cite journal | vauthors = Seo S, Herr A, Lim JW, Richardson GA, Richardson H, Kroll KL | title = Geminin regulates neuronal differentiation by antagonizing Brg1 activity | journal = Genes Dev. | volume = 19 | issue = 14 | pages = 1723–34 | year = 2005 | pmid = 16024661 | pmc = 1176010 | doi = 10.1101/gad.1319105 }}</ref> In neural precursor cells, high levels of geminin prevent terminal differentiation. When the interaction between geminin and SWI/SNF is eliminated, geminin's inhibition to this process is eliminated and neural precursors are allowed to differentiate.
*{{cite journal  | author=Kroll KL, Salic AN, Evans LM, Kirschner MW |title=Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation. |journal=Development |volume=125 |issue= 16 |pages= 3247-58 |year= 1998 |pmid= 9671596 |doi=  }}
 
*{{cite journal  | author=Wohlschlegel JA, Dwyer BT, Dhar SK, ''et al.'' |title=Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. |journal=Science |volume=290 |issue= 5500 |pages= 2309-12 |year= 2001 |pmid= 11125146 |doi= 10.1126/science.290.5500.2309 }}
== Model organisms ==
*{{cite journal  | author=Bermejo R, Vilaboa N, Calés C |title=Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization. |journal=Mol. Biol. Cell |volume=13 |issue= 11 |pages= 3989-4000 |year= 2003 |pmid= 12429841 |doi= 10.1091/mbc.E02-04-0217 }}
 
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
*{{cite journal  | author=Biswas N, Sanchez V, Spector DH |title=Human cytomegalovirus infection leads to accumulation of geminin and inhibition of the licensing of cellular DNA replication. |journal=J. Virol. |volume=77 |issue= 4 |pages= 2369-76 |year= 2003 |pmid= 12551974 |doi= }}
|+ ''Gmnn'' knockout mouse phenotype
*{{cite journal  | author=Kulartz M, Kreitz S, Hiller E, ''et al.'' |title=Expression and phosphorylation of the replication regulator protein geminin. |journal=Biochem. Biophys. Res. Commun. |volume=305 |issue= 2 |pages= 412-20 |year= 2003 |pmid= 12745091 |doi= }}
|-
*{{cite journal  | author=Mungall AJ, Palmer SA, Sims SK, ''et al.'' |title=The DNA sequence and analysis of human chromosome 6. |journal=Nature |volume=425 |issue= 6960 |pages= 805-11 |year= 2003 |pmid= 14574404 |doi= 10.1038/nature02055 }}
! Characteristic!! Phenotype
*{{cite journal  | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
|-
*{{cite journal | author=Del Bene F, Tessmar-Raible K, Wittbrodt J |title=Direct interaction of geminin and Six3 in eye development. |journal=Nature |volume=427 |issue= 6976 |pages= 745-9 |year= 2004 |pmid= 14973488 |doi= 10.1038/nature02292 }}
| [[Homozygote]] viability || bgcolor="#C40000"|Abnormal
*{{cite journal  | author=Luo L, Yang X, Takihara Y, ''et al.'' |title=The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions. |journal=Nature |volume=427 |issue= 6976 |pages= 749-53 |year= 2004 |pmid= 14973489 |doi= 10.1038/nature02305 }}
|-
*{{cite journal  | author=Sugimoto N, Tatsumi Y, Tsurumi T, ''et al.'' |title=Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. |journal=J. Biol. Chem. |volume=279 |issue= 19 |pages= 19691-7 |year= 2004 |pmid= 14993212 |doi= 10.1074/jbc.M313175200 }}
| [[Recessive]] lethal study || bgcolor="#C40000"|Abnormal
*{{cite journal | author=Melixetian M, Ballabeni A, Masiero L, ''et al.'' |title=Loss of Geminin induces rereplication in the presence of functional p53. |journal=J. Cell Biol. |volume=165 |issue= 4 |pages= 473-82 |year= 2004 |pmid= 15159417 |doi= 10.1083/jcb.200403106 }}
|-
*{{cite journal | author=Ramachandran N, Hainsworth E, Bhullar B, ''et al.'' |title=Self-assembling protein microarrays. |journal=Science |volume=305 |issue= 5680 |pages= 86-90 |year= 2004 |pmid= 15232106 |doi= 10.1126/science.1097639 }}
| Fertility || bgcolor="#488ED3"|Normal
*{{cite journal | author=Ballabeni A, Melixetian M, Zamponi R, ''et al.'' |title=Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis. |journal=EMBO J. |volume=23 |issue= 15 |pages= 3122-32 |year= 2005 |pmid= 15257290 |doi= 10.1038/sj.emboj.7600314 }}
|-
*{{cite journal  | author=Saxena S, Yuan P, Dhar SK, ''et al.'' |title=A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition. |journal=Mol. Cell |volume=15 |issue= 2 |pages= 245-58 |year= 2004 |pmid= 15260975 |doi= 10.1016/j.molcel.2004.06.045 }}
| Body weight || bgcolor="#488ED3"|Normal
*{{cite journal  | author=Zhu W, Chen Y, Dutta A |title=Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint. |journal=Mol. Cell. Biol. |volume=24 |issue= 16 |pages= 7140-50 |year= 2004 |pmid= 15282313 |doi= 10.1128/MCB.24.16.7140-7150.2004 }}
|-
*{{cite journal | author=Kulartz M, Knippers R |title=The replicative regulator protein geminin on chromatin in the HeLa cell cycle. |journal=J. Biol. Chem. |volume=279 |issue= 40 |pages= 41686-94 |year= 2004 |pmid= 15284237 |doi= 10.1074/jbc.M405798200 }}
| [[Open Field (animal test)|Anxiety]] || bgcolor="#488ED3"|Normal
}}
|-
| Neurological assessment || bgcolor="#488ED3"|Normal
|-
| Grip strength || bgcolor="#488ED3"|Normal
|-
| [[Hot plate test|Hot plate]] || bgcolor="#488ED3"|Normal
|-
| [[Dysmorphology]] || bgcolor="#488ED3"|Normal
|-
| [[Indirect calorimetry]] || bgcolor="#488ED3"|Normal
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal
|-
| [[Auditory brainstem response]] || bgcolor="#488ED3"|Normal
|-
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#488ED3"|Normal
|-
| [[Radiography]] || bgcolor="#488ED3"|Normal
|-
| Body temperature || bgcolor="#488ED3"|Normal
|-
| Eye morphology || bgcolor="#C40000"|Abnormal<ref name="Eye morphology">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MAEB/eye-morphology/ |title=Eye morphology data for Gmnn |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Clinical chemistry]] || bgcolor="#488ED3"|Normal
|-
| [[Blood plasma|Plasma]] [[immunoglobulin]]s || bgcolor="#488ED3"|Normal
|-
| [[Haematology]] || bgcolor="#488ED3"|Normal
|-
| [[Peripheral blood lymphocyte]]s || bgcolor="#488ED3"|Normal
|-
| [[Micronucleus test]] || bgcolor="#488ED3"|Normal
|-
| Heart weight || bgcolor="#488ED3"|Normal
|-
| Skin Histopathology || bgcolor="#488ED3"|Normal
|-
| Brain histopathology || bgcolor="#488ED3"|Normal
|-
| ''[[Salmonella]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Salmonella'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MAEB/salmonella-challenge/ |title=''Salmonella'' infection data for Gmnn |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| ''[[Citrobacter]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MAEB/citrobacter-challenge/ |title=''Citrobacter'' infection data for Gmnn |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal| doi = 10.1111/j.1755-3768.2010.4142.x| title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice| year = 2010| author = Gerdin AK| journal = Acta Ophthalmologica| volume = 88| issue = S248 }}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
|}
[[Model organism]]s have been used in the study of Geminin function. A conditional [[knockout mouse]] line, called ''Gmnn<sup>tm1a(KOMP)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Gmnn |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4363191 |title=Mouse Genome Informatics}}</ref> was generated as part of the [[International Knockout Mouse Consortium]] program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–342 | year = 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | year = 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | year = 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref>
 
In addition, increased genomic instability and tumorigenesis have been observed in Geminin knockout mice in both the colon and lung.<ref name=":0">{{Cite journal|last=Champeris Tsaniras|first=Spyridon|last2=Villiou|first2=Maria|last3=Giannou|first3=Anastassios D|last4=Nikou|first4=Sofia|last5=Petropoulos|first5=Michalis|last6=Pateras|first6=Ioannis S|last7=Tserou|first7=Paraskevi|last8=Karousi|first8=Foteini|last9=Lalioti|first9=Maria-Eleni|date=2018-06-27|title=Geminin ablation in vivo enhances tumorigenesis through increased genomic instability|journal=The Journal of Pathology|doi=10.1002/path.5128|issn=0022-3417|pmid=29952003}}</ref>
 
Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biol. | volume = 12 | issue = 6 | pages = 224 | year = 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref> Twenty six tests were carried out and three significant abnormalities were observed. A [[recessive]] lethal study found no [[homozygous]] [[mutant]] embryos during gestation, and therefore none survived until [[weaning]]. The remaining tests were carried out on [[heterozygous]] mutant adult mice and showed that females had abnormal [[Lens (anatomy)|lens]] morphology and [[cataract]]s.<ref name="mgp_reference" />
 
== Clinical significance ==
 
Geminin has been found to be overexpressed in several malignancies and cancer cell lines,<ref name="pmid15389519">{{cite journal | vauthors = Montanari M, Boninsegna A, Faraglia B, Coco C, Giordano A, Cittadini A, Sgambato A | title = Increased expression of geminin stimulates the growth of mammary epithelial cells and is a frequent event in human tumors | journal = J. Cell. Physiol. | volume = 202 | issue = 1 | pages = 215–22 | year = 2005 | pmid = 15389519 | doi = 10.1002/jcp.20120 }}</ref> while there is data demonstrating that Geminin acts as a tumor suppressor by safeguarding genome stability.<ref name=":0" />
 
== References ==
{{reflist|35em}}
 
== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1-2 | pages = 171–4 | year = 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1-2 | pages = 149–56 | year = 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = McGarry TJ, Kirschner MW | title = Geminin, an inhibitor of DNA replication, is degraded during mitosis | journal = Cell | volume = 93 | issue = 6 | pages = 1043–53 | year = 1998 | pmid = 9635433 | doi = 10.1016/S0092-8674(00)81209-X }}
* {{cite journal | vauthors = Kroll KL, Salic AN, Evans LM, Kirschner MW | title = Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation | journal = Development | volume = 125 | issue = 16 | pages = 3247–58 | year = 1998 | pmid = 9671596 | doi =  }}
* {{cite journal | vauthors = Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A | title = Inhibition of eukaryotic DNA replication by geminin binding to Cdt1 | journal = Science | volume = 290 | issue = 5500 | pages = 2309–12 | year = 2000 | pmid = 11125146 | doi = 10.1126/science.290.5500.2309 }}
* {{cite journal | vauthors = Bermejo R, Vilaboa N, Calés C | title = Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization | journal = Mol. Biol. Cell | volume = 13 | issue = 11 | pages = 3989–4000 | year = 2002 | pmid = 12429841 | pmc = 133609 | doi = 10.1091/mbc.E02-04-0217 }}
* {{cite journal | vauthors = Biswas N, Sanchez V, Spector DH | title = Human cytomegalovirus infection leads to accumulation of geminin and inhibition of the licensing of cellular DNA replication | journal = J. Virol. | volume = 77 | issue = 4 | pages = 2369–76 | year = 2003 | pmid = 12551974 | pmc = 141111 | doi = 10.1128/JVI.77.4.2369-2376.2003 }}
* {{cite journal | vauthors = Kulartz M, Kreitz S, Hiller E, Damoc EC, Przybylski M, Knippers R | title = Expression and phosphorylation of the replication regulator protein geminin | journal = Biochem. Biophys. Res. Commun. | volume = 305 | issue = 2 | pages = 412–20 | year = 2003 | pmid = 12745091 | doi = 10.1016/S0006-291X(03)00773-3 }}
* {{cite journal | vauthors = Del Bene F, Tessmar-Raible K, Wittbrodt J | title = Direct interaction of geminin and Six3 in eye development | journal = Nature | volume = 427 | issue = 6976 | pages = 745–9 | year = 2004 | pmid = 14973488 | doi = 10.1038/nature02292 }}
* {{cite journal | vauthors = Luo L, Yang X, Takihara Y, Knoetgen H, Kessel M | title = The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions | journal = Nature | volume = 427 | issue = 6976 | pages = 749–53 | year = 2004 | pmid = 14973489 | doi = 10.1038/nature02305 }}
* {{cite journal | vauthors = Sugimoto N, Tatsumi Y, Tsurumi T, Matsukage A, Kiyono T, Nishitani H, Fujita M | title = Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding | journal = J. Biol. Chem. | volume = 279 | issue = 19 | pages = 19691–7 | year = 2004 | pmid = 14993212 | doi = 10.1074/jbc.M313175200 }}
* {{cite journal | vauthors = Melixetian M, Ballabeni A, Masiero L, Gasparini P, Zamponi R, Bartek J, Lukas J, Helin K | title = Loss of Geminin induces rereplication in the presence of functional p53 | journal = J. Cell Biol. | volume = 165 | issue = 4 | pages = 473–82 | year = 2004 | pmid = 15159417 | pmc = 2172361 | doi = 10.1083/jcb.200403106 }}
* {{cite journal | vauthors = Ramachandran N, Hainsworth E, Bhullar B, Eisenstein S, Rosen B, Lau AY, Walter JC, LaBaer J | title = Self-assembling protein microarrays | journal = Science | volume = 305 | issue = 5680 | pages = 86–90 | year = 2004 | pmid = 15232106 | doi = 10.1126/science.1097639 }}
* {{cite journal | vauthors = Ballabeni A, Melixetian M, Zamponi R, Masiero L, Marinoni F, Helin K | title = Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis | journal = EMBO J. | volume = 23 | issue = 15 | pages = 3122–32 | year = 2004 | pmid = 15257290 | pmc = 514931 | doi = 10.1038/sj.emboj.7600314 }}
* {{cite journal | vauthors = Saxena S, Yuan P, Dhar SK, Senga T, Takeda D, Robinson H, Kornbluth S, Swaminathan K, Dutta A | title = A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition | journal = Mol. Cell | volume = 15 | issue = 2 | pages = 245–58 | year = 2004 | pmid = 15260975 | doi = 10.1016/j.molcel.2004.06.045 }}
* {{cite journal | vauthors = Zhu W, Chen Y, Dutta A | title = Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint | journal = Mol. Cell. Biol. | volume = 24 | issue = 16 | pages = 7140–50 | year = 2004 | pmid = 15282313 | pmc = 479725 | doi = 10.1128/MCB.24.16.7140-7150.2004 }}
* {{cite journal | vauthors = Kulartz M, Knippers R | title = The replicative regulator protein geminin on chromatin in the HeLa cell cycle | journal = J. Biol. Chem. | volume = 279 | issue = 40 | pages = 41686–94 | year = 2004 | pmid = 15284237 | doi = 10.1074/jbc.M405798200 }}
{{refend}}
{{refend}}
==External links==
 
== External links ==
* {{MeshName|GMNN+protein,+human}}
* {{MeshName|GMNN+protein,+human}}
{{PDB Gallery|geneid=51053}}


[[Category:Proteins]]
[[Category:Proteins]]
{{WikiDoc Sources}}
[[Category:Genes mutated in mice]]

Latest revision as of 00:57, 19 July 2018

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene.[1]

Geminin is a nuclear protein that is present in most eukaryotics and highly conserved across species. Numerous functions have been elucidated for Geminin including roles in metazoan cell cycle, cellular proliferation, cell lineage commitment, and neural differentiation.[2]

History

Geminin was originally identified as an inhibitor of DNA replication and substrate of the anaphase promoting complex (APC).[3] Coincidentally, geminin was also shown to expand the neural plate in the developing Xenopus embryo.[4]

Structure

Geminin is a nuclear protein made up of about 200 amino acids, with a molecular weight of approximately 25 kDa.[3] It contains an atypical leucine-zipper coiled-coil domain. It has no known enzymatic activity nor DNA binding motifs.

Function

Cell cycle control

Geminin is absent during G1 phase and accumulates through S, G2 phase and M phases of the cell cycle. Geminin levels drop at the metaphase / anaphase transition of mitosis when it is degraded by the Anaphase Promoting Complex (APC/C).[3]

S phase

During S phase, geminin is a negative regulator of DNA replication. In many cancer cell lines, inhibition of geminin by RNAi results in re-replication of portions of the genome, which leads to aneuploidy. In these cell lines, geminin knockdown leads to markedly slowed growth and apoptosis within several days.[5] However, the same is not true for primary and immortalized human cell lines, where other mechanisms exists to prevent DNA re-replication.[5] Since geminin knockdown leads to cell death in many cancer cell lines but not primary cell lines, it has been proposed as a potential therapeutic target for cancer treatment.[5]

Mitosis

At the start of the S-phase until late mitosis, geminin inhibits the replication factor Cdt1, preventing the assembly of the pre-replicative complex. In early G1, the APC/C complex triggers its destruction through ubiquitination. Although inhibition of geminin by RNAi leads to impairment of DNA replication during the following cell cycle in many cancer cell lines, no such cell cycle defect is seen in primary and immortalized cell lines (although Cdt1 levels are still reduced in these cells).[5]

Geminin therefore is an important player in ensuring that one and only one round of replication occurs during each cell cycle.

Developmental control

Geminin promotes early neural fate commitment by hyperacetylating the chromatin.[6] This effect allows neural genes to be accessible for transcription, promoting the expression of these genes. Ultimately, geminin allows cells uncommitted to any particular lineage to acquire neural characteristics.

Geminin has also been shown to interact with the SWI/SNF chromatin remodeling complex.[7] In neural precursor cells, high levels of geminin prevent terminal differentiation. When the interaction between geminin and SWI/SNF is eliminated, geminin's inhibition to this process is eliminated and neural precursors are allowed to differentiate.

Model organisms

Model organisms have been used in the study of Geminin function. A conditional knockout mouse line, called Gmnntm1a(KOMP)Wtsi[13][14] was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[15][16][17]

In addition, increased genomic instability and tumorigenesis have been observed in Geminin knockout mice in both the colon and lung.[18]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[11][19] Twenty six tests were carried out and three significant abnormalities were observed. A recessive lethal study found no homozygous mutant embryos during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and showed that females had abnormal lens morphology and cataracts.[11]

Clinical significance

Geminin has been found to be overexpressed in several malignancies and cancer cell lines,[20] while there is data demonstrating that Geminin acts as a tumor suppressor by safeguarding genome stability.[18]

References

  1. "Entrez Gene: GMNN geminin, DNA replication inhibitor".
  2. Kroll KL (2007). "Geminin in embryonic development: coordinating transcription and the cell cycle during differentiation". Front. Biosci. 12 (4): 1395–409. doi:10.2741/2156. PMID 17127390.
  3. 3.0 3.1 3.2 McGarry TJ, Kirschner MW (1998). "Geminin, an inhibitor of DNA replication, is degraded during mitosis". Cell. 93 (6): 1043–1053. doi:10.1016/S0092-8674(00)81209-X. PMID 9635433.
  4. Kroll KL, Salic AN, Evans LM, Kirschner MW (1998). "Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation". Development. 125 (16): 3247–58. PMID 9671596.
  5. 5.0 5.1 5.2 5.3 Zhu W, Depamphilis ML (2009). "Selective killing of cancer cells by suppression of geminin activity". Cancer Res. 69 (11): 4870–4877. doi:10.1158/0008-5472.CAN-08-4559. PMC 2749580. PMID 19487297.
  6. Yellajoshyula D, Patterson ES, Elitt MS, Kroll KL (2011). "Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state". Proc. Natl. Acad. Sci. U.S.A. 108 (8): 3294–9. doi:10.1073/pnas.1012053108. PMC 3044367. PMID 21300881.
  7. Seo S, Herr A, Lim JW, Richardson GA, Richardson H, Kroll KL (2005). "Geminin regulates neuronal differentiation by antagonizing Brg1 activity". Genes Dev. 19 (14): 1723–34. doi:10.1101/gad.1319105. PMC 1176010. PMID 16024661.
  8. "Eye morphology data for Gmnn". Wellcome Trust Sanger Institute.
  9. "Salmonella infection data for Gmnn". Wellcome Trust Sanger Institute.
  10. "Citrobacter infection data for Gmnn". Wellcome Trust Sanger Institute.
  11. 11.0 11.1 11.2 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
  12. Mouse Resources Portal, Wellcome Trust Sanger Institute.
  13. "International Knockout Mouse Consortium".
  14. "Mouse Genome Informatics".
  15. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  16. Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  17. Collins FS, Rossant J, Wurst W (2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  18. 18.0 18.1 Champeris Tsaniras, Spyridon; Villiou, Maria; Giannou, Anastassios D; Nikou, Sofia; Petropoulos, Michalis; Pateras, Ioannis S; Tserou, Paraskevi; Karousi, Foteini; Lalioti, Maria-Eleni (2018-06-27). "Geminin ablation in vivo enhances tumorigenesis through increased genomic instability". The Journal of Pathology. doi:10.1002/path.5128. ISSN 0022-3417. PMID 29952003.
  19. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
  20. Montanari M, Boninsegna A, Faraglia B, Coco C, Giordano A, Cittadini A, Sgambato A (2005). "Increased expression of geminin stimulates the growth of mammary epithelial cells and is a frequent event in human tumors". J. Cell. Physiol. 202 (1): 215–22. doi:10.1002/jcp.20120. PMID 15389519.

Further reading

External links