Geminin
Encyclopedia
Geminin, DNA replication inhibitor, also known as GMNN, is a protein
in humans encoded by the GMNN gene
.
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.
and substrate of the anaphase promoting complex (APC). Coincidentally, Geminin was also shown to expand the neural plate
in the developing Xenopus
embryo.
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).
, 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. However, the same is not true for primary and immortalized human cell lines, where other mechanisms exists to prevent 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.
or M phase, geminin stabilizes the replication factor Cdt1
by protecting it from ubiquitination and therefore subsequence proteolysis, thereby potentially promoting DNA replication during the following cell cycle. Although inhibition of geminin by RNAi leads to destabilization of Cdt1 protein and 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).
Geminin therefore is an important player in ensuring that one and only one round of replication occurs during each cell cycle.
Geminin has also been shown to interact with the SWI/SNF
chromatin remodeling complex. In neural precursor cells, high levels of Geminin prevent terminal differention. When the interaction between Geminin and SWI/SNF is eliminated, Geminin's inhibition to this process is eliminated and neural precurors are allowed to differentiate.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
in humans encoded by the GMNN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
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.
History
Geminin was originally identified as an inhibitor of DNA replicationDNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and substrate of the anaphase promoting complex (APC). Coincidentally, Geminin was also shown to expand the neural plate
Neural plate
In human embryology, formation of neural plate is the first step of neurulation. It is created by a flat thickening opposite to the primitive streak of the ectoderm.-Development:...
in the developing Xenopus
Xenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
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.Cell cycle control
Geminin is absent during G1 phaseG1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
and accumulates through S
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
, G2 phase
G2 phase
G2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...
and M phases
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
of the cell cycle. Geminin levels drop at the metaphase
Metaphase
Metaphase, from the ancient Greek μετά and φάσις , is a stage of mitosis in the eukaryotic cell cycle in which condensed & highly coiled chromosomes, carrying genetic information, align in the middle of the cell before being separated into each of the two daughter cells...
/ anaphase
Anaphase
Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....
transition of mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
when it is degraded by the Anaphase Promoting Complex (APC).
S phase
During S phaseS phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
, geminin is a negative regulator of DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
. In many cancer cell lines, inhibition of geminin by RNAi
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
results in re-replication of portions of the genome, which leads to aneuploidy
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
. In these cell lines, geminin knockdown leads to markedly slowed growth and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
within several days. However, the same is not true for primary and immortalized human cell lines, where other mechanisms exists to prevent 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
During mitosisMitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
or M phase, geminin stabilizes the replication factor Cdt1
DNA replication factor CDT1
DNA replication factor Cdt1 is a protein that in humans is encoded by the CDT1 gene.The protein encoded by this gene is a key licensing factor which, along with the protein Cdc6, functions to license DNA by forming the pre-replication complex...
by protecting it from ubiquitination and therefore subsequence proteolysis, thereby potentially promoting DNA replication during the following cell cycle. Although inhibition of geminin by RNAi leads to destabilization of Cdt1 protein and 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).
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. 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
SWI/SNF
SWI/SNF is a yeast nucleosome remodeling complex composed of several proteins – products of the SWI and SNF genes as well as several other polypeptides...
chromatin remodeling complex. In neural precursor cells, high levels of Geminin prevent terminal differention. When the interaction between Geminin and SWI/SNF is eliminated, Geminin's inhibition to this process is eliminated and neural precurors are allowed to differentiate.