Geminin

Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene. A nuclear protein present in most eukaryotes 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. One example of its function is the inhibition of Cdt1.

GMNN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1T6F, 1UII, 2LP0, 2WVR, 4BRY
Identifiers
Aliases	GMNN, Gem, MGORS6, geminin, DNA replication inhibitor, geminin DNA replication inhibitor
External IDs	OMIM: 602842; MGI: 1927344; HomoloGene: 9292; GeneCards: GMNN; OMA:GMNN - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6p22.3 Start 24,774,931 bp End 24,786,099 bp
Gene location (Mouse) Chr. Chromosome 13 (mouse) Band 13|13 A3.1 Start 24,935,828 bp End 24,945,906 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in oocyte body of pancreas secondary oocyte gonad mucosa of transverse colon ventricular zone embryo rectum ganglionic eminence mucosa of sigmoid colon Top expressed in primitive streak fetal liver hematopoietic progenitor cell morula yolk sac Paneth cell embryo embryo medial ganglionic eminence blastocyst epiblast More reference expression data BioGPS More reference expression data
Gene ontology Molecular function histone deacetylase binding protein binding transcription corepressor activity chromatin binding Cellular component cytoplasm nucleus nucleoplasm cytosol Biological process animal organ morphogenesis cell cycle negative regulation of cell cycle negative regulation of DNA replication negative regulation of transcription, DNA-templated regulation of DNA replication positive regulation of chromatin binding DNA replication preinitiation complex assembly negative regulation of DNA-dependent DNA replication protein-containing complex assembly G1/S transition of mitotic cell cycle Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 51053 57441 Ensembl ENSG00000112312 ENSMUSG00000006715 UniProt O75496 O88513 RefSeq (mRNA) NM_001251989 NM_001251990 NM_001251991 NM_015895 NM_020567 RefSeq (protein) NP_001238918 NP_001238919 NP_001238920 NP_056979 NP_065592 Location (UCSC) Chr 6: 24.77 – 24.79 Mb Chr 13: 24.94 – 24.95 Mb PubMed search
Wikidata
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History

Geminin was originally identified as an inhibitor of DNA replication and substrate of the anaphase-promoting complex. Coincidentally, geminin was also shown to expand the neural plate in the developing Xenopus embryo.

Structure

Geminin is a nuclear protein made up of about 200 amino acids, with a molecular weight of approximately 25 kDa. 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.

S phase

During S phase, geminin is a negative regulator of DNA replication. In many cancer cell lines, inhibition of geminin by RNA interference 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. However, the same is not true for primary and immortalized human cell lines, where other mechanisms exists to prevent DNA re-replication. 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.

Mitosis

At the start of the S-phase until late mitosis, geminin inhibits the replication factor Cdt1, preventing the assembly of the pre-replication complex. In early G1, the anaphase promoting complex triggers its destruction through ubiquitination.

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

Developmental control

Geminin promotes early neural fate commitment by hyperacetylating chromatin. 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. 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.

Clinical significance

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

Further reading

• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• 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. S2CID 235485.
• 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): 3247–3258. doi:10.1242/dev.125.16.3247. PMID 9671596.
• Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A (2000). "Inhibition of eukaryotic DNA replication by geminin binding to Cdt1". Science. 290 (5500): 2309–2312. Bibcode:2000Sci...290.2309W. doi:10.1126/science.290.5500.2309. PMID 11125146.
• Bermejo R, Vilaboa N, Calés C (2002). "Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization". Molecular Biology of the Cell. 13 (11): 3989–4000. doi:10.1091/mbc.E02-04-0217. PMC 133609. PMID 12429841.
• Biswas N, Sanchez V, Spector DH (2003). "Human cytomegalovirus infection leads to accumulation of geminin and inhibition of the licensing of cellular DNA replication". Journal of Virology. 77 (4): 2369–2376. doi:10.1128/JVI.77.4.2369-2376.2003. PMC 141111. PMID 12551974.
• Kulartz M, Kreitz S, Hiller E, Damoc EC, Przybylski M, Knippers R (2003). "Expression and phosphorylation of the replication regulator protein geminin". Biochemical and Biophysical Research Communications. 305 (2): 412–420. doi:10.1016/S0006-291X(03)00773-3. PMID 12745091.
• Del Bene F, Tessmar-Raible K, Wittbrodt J (2004). "Direct interaction of geminin and Six3 in eye development". Nature. 427 (6976): 745–749. Bibcode:2004Natur.427..745B. doi:10.1038/nature02292. PMID 14973488. S2CID 4410030.
• Luo L, Yang X, Takihara Y, Knoetgen H, Kessel M (2004). "The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions". Nature. 427 (6976): 749–753. Bibcode:2004Natur.427..749L. doi:10.1038/nature02305. hdl:11858/00-001M-0000-0012-EE32-1. PMID 14973489. S2CID 8020382.
• Sugimoto N, Tatsumi Y, Tsurumi T, Matsukage A, Kiyono T, Nishitani H, Fujita M (2004). "Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding". Journal of Biological Chemistry. 279 (19): 19691–19697. doi:10.1074/jbc.M313175200. PMID 14993212.
• Melixetian M, Ballabeni A, Masiero L, Gasparini P, Zamponi R, Bartek J, Lukas J, Helin K (2004). "Loss of Geminin induces rereplication in the presence of functional p53". Journal of Cell Biology. 165 (4): 473–482. doi:10.1083/jcb.200403106. PMC 2172361. PMID 15159417.
• Ramachandran N, Hainsworth E, Bhullar B, Eisenstein S, Rosen B, Lau AY, Walter JC, LaBaer J (2004). "Self-assembling protein microarrays". Science. 305 (5680): 86–90. Bibcode:2004Sci...305...86R. doi:10.1126/science.1097639. PMID 15232106. S2CID 20936301.
• Ballabeni A, Melixetian M, Zamponi R, Masiero L, Marinoni F, Helin K (2004). "Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis". EMBO Journal. 23 (15): 3122–3132. doi:10.1038/sj.emboj.7600314. PMC 514931. PMID 15257290.
• Saxena S, Yuan P, Dhar SK, Senga T, Takeda D, Robinson H, Kornbluth S, Swaminathan K, Dutta A (2004). "A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition". Mol. Cell. 15 (2): 245–258. doi:10.1016/j.molcel.2004.06.045. PMID 15260975.
• Zhu W, Chen Y, Dutta A (2004). "Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint". Molecular and Cellular Biology. 24 (16): 7140–7150. doi:10.1128/MCB.24.16.7140-7150.2004. PMC 479725. PMID 15282313.
• Kulartz M, Knippers R (2004). "The replicative regulator protein geminin on chromatin in the HeLa cell cycle". Journal of Biological Chemistry. 279 (40): 41686–41694. doi:10.1074/jbc.M405798200. PMID 15284237.

External links

• GMNN+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: O75496 (Human Geminin) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: O88513 (Mouse Geminin) at the PDBe-KB.