Biology:Geminin

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Short description: Nuclear protein inhibiting DNA replication


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene.[1] 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.[2] One example of its function is the inhibition of Cdt1.[3]

History

Geminin was originally identified as an inhibitor of DNA replication and substrate of the anaphase-promoting complex.[4] Coincidentally, geminin was also shown to expand the neural plate in the developing Xenopus embryo.[5]

Structure

Geminin is a nuclear protein made up of about 200 amino acids, with a molecular weight of approximately 25 kDa.[4] 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.[4]

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.[6] However, the same is not true for primary and immortalized human cell lines, where other mechanisms exists to prevent DNA re-replication.[6] 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.[6]

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.[7] 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.[8] 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,[9] while there is data demonstrating that geminin acts as a tumor suppressor by safeguarding genome stability.[10]

References

  1. ↑ "Entrez Gene: GMNN geminin, DNA replication inhibitor". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51053. 
  2. ↑ "Geminin in embryonic development: coordinating transcription and the cell cycle during differentiation". Frontiers in Bioscience 12 (4): 1395–1409. 2007. doi:10.2741/2156. PMID 17127390. 
  3. ↑ Alberts, Bruce (18 November 2014). Molecular biology of the cell (Sixth ed.). New York, NY. pp. 975. ISBN 978-0-8153-4432-2. OCLC 887605755. https://www.worldcat.org/oclc/887605755. 
  4. ↑ 4.0 4.1 4.2 "Geminin, an inhibitor of DNA replication, is degraded during mitosis". Cell 93 (6): 1043–1053. 1998. doi:10.1016/S0092-8674(00)81209-X. PMID 9635433. 
  5. ↑ "Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation". Development 125 (16): 3247–3258. 1998. doi:10.1242/dev.125.16.3247. PMID 9671596. 
  6. ↑ 6.0 6.1 6.2 "Selective killing of cancer cells by suppression of geminin activity". Cancer Research 69 (11): 4870–4877. 2009. doi:10.1158/0008-5472.CAN-08-4559. PMID 19487297. 
  7. ↑ "Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state". Proceedings of the National Academy of Sciences USA 108 (8): 3294–3299. 2011. doi:10.1073/pnas.1012053108. PMID 21300881. Bibcode: 2011PNAS..108.3294Y. 
  8. ↑ "Geminin regulates neuronal differentiation by antagonizing Brg1 activity". Genes & Development 19 (14): 1723–34. 2005. doi:10.1101/gad.1319105. PMID 16024661. 
  9. ↑ "Increased expression of geminin stimulates the growth of mammary epithelial cells and is a frequent event in human tumors". Journal of Cellular Physiology 202 (1): 215–22. 2005. doi:10.1002/jcp.20120. PMID 15389519. 
  10. ↑ Champeris Tsaniras, Spyridon; Villiou, Maria; Giannou, Anastassios D; Nikou, Sofia; Petropoulos, Michalis; Pateras, Ioannis S; Tserou, Paraskevi; Karousi, Foteini et al. (2018-06-27). "Geminin ablation in vivo enhances tumorigenesis through increased genomic instability". Journal of Pathology 246 (2): 134–140. doi:10.1002/path.5128. ISSN 0022-3417. PMID 29952003. 

Further reading

External links



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