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 growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
, 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
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
when it is degraded by the
anaphase-promoting complex.
S phase
During
S phase
S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
, 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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
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 organism
A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...
s 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
The International Knockout Mouse Consortium (IKMC) is a scientific endeavour to produce a collection of mouse embryonic stem cell lines that together lack every gene in the genome, and then to distribute the cells to scientific researchers to crea ...
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.
References
Further reading
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External links
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{{PDB Gallery, geneid=51053
Proteins
Genes mutated in mice