TOP3A

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells.

File:Homologous Recombination.jpg

Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and see Figure). The pathway leading to a NCO is referred to as Synthesis-dependent strand annealing (SDSA).

In the plant Arabidopsis thaliana, multiple mechanisms limit meiotic COs.{{cite journal | vauthors = Séguéla-Arnaud M, Crismani W, Larchevêque C, Mazel J, Froger N, Choinard S, Lemhemdi A, Macaisne N, Van Leene J, Gevaert K, De Jaeger G, Chelysheva L, Mercier R | title = Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 15 | pages = 4713–8 | date = Apr 2015 | pmid = 25825745 | pmc = 4403193 | doi = 10.1073/pnas.1423107112 | bibcode = 2015PNAS..112.4713S | doi-access = free }} During meiosis TOP3A and RECQ4A/B helicase antagonize formation of COs in parallel to FANCM helicase. Sequela-Arnaud et al. suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.

In the budding yeast Saccharomyces cerevisiae, the topoisomerase III (TOP3)-RMI1 heterodimer (that catalyzes DNA single-strand passage) forms a conserved complex with Sgs1 helicase (an ortholog of the human Bloom syndrome helicase). This complex promotes early formation of NCO recombinants during meiosis{{cite journal | vauthors = Kaur H, De Muyt A, Lichten M | title = Top3-Rmi1 DNA single-strand decatenase is integral to the formation and resolution of meiotic recombination intermediates | journal = Molecular Cell | volume = 57 | issue = 4 | pages = 583–94 | date = Feb 2015 | pmid = 25699707 | doi = 10.1016/j.molcel.2015.01.020 | pmc=4338413}} The TOP3-RMI1 strand passage activity appears to have two important functions during meiosis. First, strand passage activity is employed early in coordination with Sgs1 helicase to promote proper recombination pathway choice. Second, strand passage activity is used later, independently of Sgs1 helicase, to prevent the persistence of unresolvable strand entanglements in recombination intermediates.

TOP3A has been shown to interact with Bloom syndrome protein.{{cite journal | vauthors = Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID | title = The Bloom's syndrome gene product interacts with topoisomerase III | journal = The Journal of Biological Chemistry | volume = 275 | issue = 13 | pages = 9636–44 | date = Mar 2000 | pmid = 10734115 | doi = 10.1074/jbc.275.13.9636 | doi-access = free }}{{cite journal | vauthors = Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP | title = Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha | journal = Nucleic Acids Research | volume = 29 | issue = 15 | pages = 3172–80 | date = Aug 2001 | pmid = 11470874 | pmc = 55826 | doi = 10.1093/nar/29.15.3172 }}{{cite journal | vauthors = Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA | title = Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability | journal = Human Molecular Genetics | volume = 10 | issue = 12 | pages = 1287–98 | date = Jun 2001 | pmid = 11406610 | doi = 10.1093/hmg/10.12.1287 | doi-access = free }}{{cite journal | vauthors = Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA | title = Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity | journal = The Journal of Biological Chemistry | volume = 275 | issue = 31 | pages = 23500–8 | date = Aug 2000 | pmid = 10825162 | doi = 10.1074/jbc.M001557200 | doi-access = free | hdl = 10026.1/10318 | hdl-access = free }}

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• {{cite journal | vauthors = Hanai R, Caron PR, Wang JC | title = Human TOP3: a single-copy gene encoding DNA topoisomerase III | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 8 | pages = 3653–7 | date = Apr 1996 | pmid = 8622991 | pmc = 39666 | doi = 10.1073/pnas.93.8.3653 | bibcode = 1996PNAS...93.3653H | doi-access = free }}
• {{cite journal | vauthors = Fritz E, Elsea SH, Patel PI, Meyn MS | title = Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 9 | pages = 4538–42 | date = Apr 1997 | pmid = 9114025 | pmc = 20758 | doi = 10.1073/pnas.94.9.4538 | bibcode = 1997PNAS...94.4538F | doi-access = free }}
• {{cite journal | vauthors = Kim JC, Yoon JB, Koo HS, Chung IK | title = Cloning and characterization of the 5'-flanking region for the human topoisomerase III gene | journal = The Journal of Biological Chemistry | volume = 273 | issue = 40 | pages = 26130–7 | date = Oct 1998 | pmid = 9748294 | doi = 10.1074/jbc.273.40.26130 | doi-access = free }}
• {{cite journal | vauthors = Goulaouic H, Roulon T, Flamand O, Grondard L, Lavelle F, Riou JF | title = Purification and characterization of human DNA topoisomerase IIIalpha | journal = Nucleic Acids Research | volume = 27 | issue = 12 | pages = 2443–50 | date = Jun 1999 | pmid = 10352172 | pmc = 148446 | doi = 10.1093/nar/27.12.2443 }}
• {{cite journal | vauthors = Shimamoto A, Nishikawa K, Kitao S, Furuichi Y | title = Human RecQ5beta, a large isomer of RecQ5 DNA helicase, localizes in the nucleoplasm and interacts with topoisomerases 3alpha and 3beta | journal = Nucleic Acids Research | volume = 28 | issue = 7 | pages = 1647–55 | date = Apr 2000 | pmid = 10710432 | pmc = 102787 | doi = 10.1093/nar/28.7.1647 }}
• {{cite journal | vauthors = Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID | title = The Bloom's syndrome gene product interacts with topoisomerase III | journal = The Journal of Biological Chemistry | volume = 275 | issue = 13 | pages = 9636–44 | date = Mar 2000 | pmid = 10734115 | doi = 10.1074/jbc.275.13.9636 | doi-access = free }}
• {{cite journal | vauthors = Lin CW, Darzynkiewicz Z, Li X, Traganos F, Bedner E, Tse-Dinh YC | title = Differential expression of human topoisomerase IIIalpha during the cell cycle progression in HL-60 leukemia cells and human peripheral blood lymphocytes | journal = Experimental Cell Research | volume = 256 | issue = 1 | pages = 225–36 | date = Apr 2000 | pmid = 10739669 | doi = 10.1006/excr.1999.4778 }}
• {{cite journal | vauthors = Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA | title = Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity | journal = The Journal of Biological Chemistry | volume = 275 | issue = 31 | pages = 23500–8 | date = Aug 2000 | pmid = 10825162 | doi = 10.1074/jbc.M001557200 | doi-access = free | hdl = 10026.1/10318 | hdl-access = free }}
• {{cite journal | vauthors = Lodge AJ, Anderson JJ, Ng SW, Fenwick F, Steward M, Haugk B, Horne CH, Angus B | title = Expression of topoisomerase IIIalpha in normal and neoplastic tissues determined by immunohistochemistry using a novel monoclonal antibody | journal = British Journal of Cancer | volume = 83 | issue = 4 | pages = 498–505 | date = Aug 2000 | pmid = 10945498 | pmc = 2374664 | doi = 10.1054/bjoc.2000.1293 }}
• {{cite journal | vauthors = Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA | title = Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability | journal = Human Molecular Genetics | volume = 10 | issue = 12 | pages = 1287–98 | date = Jun 2001 | pmid = 11406610 | doi = 10.1093/hmg/10.12.1287 | doi-access = free }}
• {{cite journal | vauthors = Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP | title = Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha | journal = Nucleic Acids Research | volume = 29 | issue = 15 | pages = 3172–80 | date = Aug 2001 | pmid = 11470874 | pmc = 55826 | doi = 10.1093/nar/29.15.3172 }}
• {{cite journal | vauthors = Bi W, Yan J, Stankiewicz P, Park SS, Walz K, Boerkoel CF, Potocki L, Shaffer LG, Devriendt K, Nowaczyk MJ, Inoue K, Lupski JR | title = Genes in a refined Smith-Magenis syndrome critical deletion interval on chromosome 17p11.2 and the syntenic region of the mouse | journal = Genome Research | volume = 12 | issue = 5 | pages = 713–28 | date = May 2002 | pmid = 11997338 | pmc = 186594 | doi = 10.1101/gr.73702 }}
• {{cite journal | vauthors = Wang Y, Lyu YL, Wang JC | title = Dual localization of human DNA topoisomerase IIIalpha to mitochondria and nucleus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 19 | pages = 12114–9 | date = Sep 2002 | pmid = 12209014 | pmc = 129407 | doi = 10.1073/pnas.192449499 | bibcode = 2002PNAS...9912114W | doi-access = free }}
• {{cite journal | vauthors = Wu L, Hickson ID | title = The Bloom's syndrome helicase stimulates the activity of human topoisomerase IIIalpha | journal = Nucleic Acids Research | volume = 30 | issue = 22 | pages = 4823–9 | date = Nov 2002 | pmid = 12433984 | pmc = 137159 | doi = 10.1093/nar/gkf611 }}
• {{cite journal | vauthors = Meetei AR, de Winter JP, Medhurst AL, Wallisch M, Waisfisz Q, van de Vrugt HJ, Oostra AB, Yan Z, Ling C, Bishop CE, Hoatlin ME, Joenje H, Wang W | title = A novel ubiquitin ligase is deficient in Fanconi anemia | journal = Nature Genetics | volume = 35 | issue = 2 | pages = 165–70 | date = Oct 2003 | pmid = 12973351 | doi = 10.1038/ng1241 | s2cid = 10149290 }}
• {{cite journal | vauthors = Jiao R, Bachrati CZ, Pedrazzi G, Kuster P, Petkovic M, Li JL, Egli D, Hickson ID, Stagljar I | title = Physical and functional interaction between the Bloom's syndrome gene product and the largest subunit of chromatin assembly factor 1 | journal = Molecular and Cellular Biology | volume = 24 | issue = 11 | pages = 4710–9 | date = Jun 2004 | pmid = 15143166 | pmc = 416397 | doi = 10.1128/MCB.24.11.4710-4719.2004 }}
• {{cite journal | vauthors = Yin J, Sobeck A, Xu C, Meetei AR, Hoatlin M, Li L, Wang W | title = BLAP75, an essential component of Bloom's syndrome protein complexes that maintain genome integrity | journal = The EMBO Journal | volume = 24 | issue = 7 | pages = 1465–76 | date = Apr 2005 | pmid = 15775963 | pmc = 1142546 | doi = 10.1038/sj.emboj.7600622 }}

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