This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison.
The TOP3β Protein
The nucleus of each individual cell in the human body contains a full set of human chromosomes, that means 23 pairs of chromosomes which makes 46 total chromosomes. When stretched end to end, all of these chromosomes would equate to 2 meters of DNA, which is far to large to fit into the nucleus. So, the DNA is condensed to fit into the nucleus--first it is wrapped around protein nucleosomes like beads on a string, then those beads are coiled into a helical structure, which is supercoiled. When the cell needs to access the DNA (such as during replication or transcription), the cell uses proteins called DNA topoisomerases to unwind small segments of the DNA at a time while the rest of the DNA remains tightly compacted [8]. This is one of the numerous functions of DNA topoisomerases. See the video below for a visual description of topoisomerases.
Youtube 2009. Topoisomerase 1 and 2 can be found and this link: http://www.youtube.com/watch?v=EYGrElVyHnU
There are two classes of DNA topoisomerases, Class I and Class II. Class I DNA topoisomerases break only one strand of the DNA double helix to relax over- or under-wound DNA during transcription and replication. Topoisomerase then reseals the DNA strand. Topoisomerase I, III, and V are all Class I topoisomerases [8]. Class II topoisomerases break both DNA strands at the same time, relax tension in the double helix, and then reseal the strands. Topoisomerase II, IV, and VI are all in Class II [8]. Within both classes are A and B subsets. The human protein, DNA Topoisomerase III β (TOP3β), is a Class IA topoisomerase [10].
Along with its unwinding function during replication and transcription, TOP3β plays an important role in recombination, cell aging, and the maintenance of genome stability [9]. TOP3β has also recently been found to directly bind to mRNA and is a component of cystosolic messenger ribonucleoproteins (mRNPs) [10]. In this study published in 2013, TOP3β recruitment to mRNPs was found to be coupled to the recruitment of Fragile X Mental Retardation Protein (FMRP), an RNA binding protein that normally inhibits the translation of neuronal mRNA. When FMRP is mutated (through a missense mutation in the FMR1 gene), proteins are produced from these mRNA's in excessive amounts and cause Fragile X syndrome, which is one of the causes of autism. TOP3β was found to be involved in the metabolism, or degradation, of FMRP-bound mRNAs. Thus, TOP3β was found to play an important role in human neurodevelopment. The deletion of the TOP3B gene, through a rare 22q11.22 deletion that wholly contains this gene, was found to be associated, acting in tandem with environmental factors, with schizophrenia and cognitive impairment through this study as well [10].
References
[8] McDowall, J. InterPro. (2014). DNA Topoisomerase. Retrieved Feb. 5, 2014 from http://www.ebi.ac.uk/interpro/potm/2006_1/Page1.htm
[9] Gene Cards. (Last Update Jan. 23, 2014). Topoisomerase (DNA) III Beta. Retrieved Feb. 5, 2014 from http://www.genecards.org/cgi-bin/carddisp.pl?gene=TOP3B
[10] Stoll, G., Pietilainen, OP., Linder, B., et. al. Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat. Neurosci. 2013 Sep;16(9):1228-37. doi: 10.1038/nn.3484. Epub 2013 Aug 4. PubMed PMID: 23912948.
[9] Gene Cards. (Last Update Jan. 23, 2014). Topoisomerase (DNA) III Beta. Retrieved Feb. 5, 2014 from http://www.genecards.org/cgi-bin/carddisp.pl?gene=TOP3B
[10] Stoll, G., Pietilainen, OP., Linder, B., et. al. Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat. Neurosci. 2013 Sep;16(9):1228-37. doi: 10.1038/nn.3484. Epub 2013 Aug 4. PubMed PMID: 23912948.