geminin

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.{{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 = 3247–3258 | year = 1998 | doi = 10.1242/dev.125.16.3247 | pmid = 9671596 }}

Geminin is a nuclear protein made up of about 200 amino acids, with a molecular weight of approximately 25 kDa.{{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 | s2cid = 235485 | doi-access = free }} It contains an atypical leucine zipper coiled-coil domain. It has no known enzymatic activity nor DNA binding motifs.

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.

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.{{cite journal | vauthors = Zhu W, Depamphilis ML | title = Selective killing of cancer cells by suppression of geminin activity | journal = Cancer Research | volume = 69 | issue = 11 | pages = 4870–4877 | year = 2009 | pmid = 19487297 | pmc = 2749580 | doi = 10.1158/0008-5472.CAN-08-4559 }} 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.

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.

Geminin promotes early neural fate commitment by hyperacetylating chromatin.{{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 = Proceedings of the National Academy of Sciences USA | volume = 108 | issue = 8 | pages = 3294–3299 | year = 2011 | pmid = 21300881 | pmc = 3044367 | doi = 10.1073/pnas.1012053108 | bibcode = 2011PNAS..108.3294Y | doi-access = free }} 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.{{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 & Development | volume = 19 | issue = 14 | pages = 1723–34 | year = 2005 | pmid = 16024661 | pmc = 1176010 | doi = 10.1101/gad.1319105 }} 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.

Geminin has been found to be overexpressed in several malignancies and cancer cell lines,{{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 = Journal of Cellular Physiology | volume = 202 | issue = 1 | pages = 215–22 | year = 2005 | pmid = 15389519 | doi = 10.1002/jcp.20120 | s2cid = 28652986 }} while there is data demonstrating that geminin acts as a tumor suppressor by safeguarding genome stability.{{Cite journal |last1=Champeris Tsaniras |first1=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=Journal of Pathology |volume=246 |issue=2 |pages=134–140 |doi=10.1002/path.5128 |issn=0022-3417 |pmid=29952003 |s2cid=49474213}}

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{{refend}}

• {{MeshName|GMNN+protein,+human}}
• {{PDBe-KB2|O75496|Human Geminin}}
• {{PDBe-KB2|O88513|Mouse Geminin}}

{{PDB Gallery|geneid=51053}}

Category:Proteins

Category:Genes mutated in mice