Geminin

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
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 embryo rectum ganglionic eminence palpebral conjunctiva skin of abdomen endometrium cancellous bone Top expressed in primitive streak morula yolk sac Paneth cell medial ganglionic eminence abdominal wall endocardial cushion spermatocyte hair follicle thymus 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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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.

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.

Model organisms

Model organisms have been used in the study of geminin function. A conditional knockout mouse line, called Gmnn^{tm1a(KOMP)Wtsi} 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.

In addition, increased genomic instability and tumorigenesis have been observed in geminin knockout mice in both the colon and lung.

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. 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.

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

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.