Geminin
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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
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Abnormal |
| Recessive lethal study | Abnormal |
| Fertility | Normal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Body temperature | Normal |
| Eye morphology | Abnormal[8] |
| Clinical chemistry | Normal |
| Plasma immunoglobulins | Normal |
| Haematology | Normal |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Skin Histopathology | Normal |
| Brain histopathology | Normal |
| Salmonella infection | Normal[9] |
| Citrobacter infection | Normal[10] |
| All tests and analysis from[11][12] |
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
- ↑ "Entrez Gene: GMNN geminin, DNA replication inhibitor".
- ↑ 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.
- ↑ 3.0 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.
- ↑ 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.
- ↑ 5.0 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.
- ↑ 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.
- ↑ 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.
- ↑ "Eye morphology data for Gmnn". Wellcome Trust Sanger Institute.
- ↑ "Salmonella infection data for Gmnn". Wellcome Trust Sanger Institute.
- ↑ "Citrobacter infection data for Gmnn". Wellcome Trust Sanger Institute.
- ↑ 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.
- ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
- ↑ "International Knockout Mouse Consortium".
- ↑ "Mouse Genome Informatics".
- ↑ 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.
- ↑ Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ↑ 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.
- ↑ 18.0 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.
- ↑ 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.
- ↑ 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
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. 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): 149–56. 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): 1043–53. doi:10.1016/S0092-8674(00)81209-X. PMID 9635433.
- 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.
- 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): 2309–12. 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". Mol. Biol. 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". J. Virol. 77 (4): 2369–76. 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". Biochem. Biophys. Res. Commun. 305 (2): 412–20. 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): 745–9. doi:10.1038/nature02292. PMID 14973488.
- 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): 749–53. doi:10.1038/nature02305. PMID 14973489.
- 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". J. Biol. Chem. 279 (19): 19691–7. 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". J. Cell Biol. 165 (4): 473–82. 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. doi:10.1126/science.1097639. PMID 15232106.
- 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 J. 23 (15): 3122–32. 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): 245–58. 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". Mol. Cell. Biol. 24 (16): 7140–50. 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". J. Biol. Chem. 279 (40): 41686–94. doi:10.1074/jbc.M405798200. PMID 15284237.
External links
- GMNN+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
