TOP3A

Topoisomerase (DNA) III alpha
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TOP3A ; TOP3; ZGRF7
External IDs OMIM: 601243 MGI: 1197527 HomoloGene: 3394 GeneCards: TOP3A Gene
EC number 5.99.1.2
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 7156 21975
Ensembl ENSG00000177302 ENSMUSG00000002814
UniProt Q13472 O70157
RefSeq (mRNA) NM_004618 NM_009410
RefSeq (protein) NP_004609 NP_033436
Location (UCSC) Chr 17:
18.27 – 18.32 Mb		 Chr 11:
60.74 – 60.78 Mb
PubMed search

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.[2]

Meiosis

A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

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.[3] Sequela-Arnaud et al.[3] 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.[4] 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]

References

  1. ↑ Elsea SH, Fritz E, Schoener-Scott R, Meyn MS, Patel PI (Jan 1998). "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. doi:10.1002/(SICI)1096-8628(19980106)75:1<104::AID-AJMG21>3.0.CO;2-P. PMID 9450867.
  2. 1 2 "Entrez Gene: TOP3A topoisomerase (DNA) III alpha".
  3. 1 2 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 (Apr 2015). "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. doi:10.1073/pnas.1423107112. PMC 4403193. PMID 25825745.
  4. 1 2 Kaur H, De Muyt A, Lichten M (Feb 2015). "Top3-Rmi1 DNA single-strand decatenase is integral to the formation and resolution of meiotic recombination intermediates". Molecular Cell 57 (4): 583–94. doi:10.1016/j.molcel.2015.01.020. PMID 25699707.
  5. ↑ Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID (Mar 2000). "The Bloom's syndrome gene product interacts with topoisomerase III". The Journal of Biological Chemistry 275 (13): 9636–44. doi:10.1074/jbc.275.13.9636. PMID 10734115.
  6. ↑ Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP (Aug 2001). "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. doi:10.1093/nar/29.15.3172. PMC 55826. PMID 11470874.
  7. ↑ Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA (Jun 2001). "Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability". Human Molecular Genetics 10 (12): 1287–98. doi:10.1093/hmg/10.12.1287. PMID 11406610.
  8. ↑ Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA (Aug 2000). "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. doi:10.1074/jbc.M001557200. PMID 10825162.

Further reading

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