TOP3A explained

DNA topoisomerase 3-alpha is an enzyme that in humans is encoded by the TOP3A gene.[1] [2]

Function

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.

Meiosis

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.[3] 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[4] 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.

Interactions

TOP3A has been shown to interact with Bloom syndrome protein.[5] [6] [7] [8]

Further reading

Notes and References

  1. Elsea SH, Fritz E, Schoener-Scott R, Meyn MS, Patel PI . Gene for topoisomerase III maps within the Smith-Magenis syndrome critical region: analysis of cell-cycle distribution and radiation sensitivity . American Journal of Medical Genetics . 75 . 1 . 104–8 . Jan 1998 . 9450867 . 10.1002/(SICI)1096-8628(19980106)75:1<104::AID-AJMG21>3.0.CO;2-P .
  2. Web site: Entrez Gene: TOP3A topoisomerase (DNA) III alpha.
  3. 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 . Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM . Proceedings of the National Academy of Sciences of the United States of America . 112 . 15 . 4713–8 . Apr 2015 . 25825745 . 4403193 . 10.1073/pnas.1423107112 . 2015PNAS..112.4713S . free .
  4. Kaur H, De Muyt A, Lichten M . Top3-Rmi1 DNA single-strand decatenase is integral to the formation and resolution of meiotic recombination intermediates . Molecular Cell . 57 . 4 . 583–94 . Feb 2015 . 25699707 . 10.1016/j.molcel.2015.01.020 . 4338413.
  5. Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID . The Bloom's syndrome gene product interacts with topoisomerase III . The Journal of Biological Chemistry . 275 . 13 . 9636–44 . Mar 2000 . 10734115 . 10.1074/jbc.275.13.9636 . free .
  6. Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP . Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha . Nucleic Acids Research . 29 . 15 . 3172–80 . Aug 2001 . 11470874 . 55826 . 10.1093/nar/29.15.3172 .
  7. Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA . Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability . Human Molecular Genetics . 10 . 12 . 1287–98 . Jun 2001 . 11406610 . 10.1093/hmg/10.12.1287 . free .
  8. Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA . Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity . The Journal of Biological Chemistry . 275 . 31 . 23500–8 . Aug 2000 . 10825162 . 10.1074/jbc.M001557200 . free . 10026.1/10318 . free .

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