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== General Description ==
== General Description ==
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Human polymerase θ (pol θ) is large, 290kD enzyme consisting of three distinct domains <ref>PMID:23219161</ref><ref name="Seki">PMID:14576298</ref>. An N-terminal helicase-like domain, whose exact cellular functions are a topic of on-going debate and research<ref>PMID:29058711</ref><ref>PMID:29444826</ref>, is linked to a C-terminal, family A DNA polymerase domain by a large and disordered central region<ref name="Seki">. Notably, pol θ is the only known human polymerase to contain a polymerase and helicase domain in one molecule (5). Crystal structures have been solved for the apo form of the [http://www.rcsb.org/structure/5a9j helicase-like domain] (6) and the ternary complex of the [http://http://www.rcsb.org/structure/4X0P polymerase domain] (5). The focus of this wiki is the polymerase domain.
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Human polymerase θ (pol θ) is large, 290kD enzyme consisting of three distinct domains <ref>PMID:23219161</ref><ref name="Seki">PMID:14576298</ref>. An N-terminal helicase-like domain, whose exact cellular functions are a topic of on-going debate and research<ref>PMID:29058711</ref><ref>PMID:29444826</ref>, is linked to a C-terminal, family A DNA polymerase domain by a large and disordered central region<ref name="Seki" />. Notably, pol θ is the only known human polymerase to contain a polymerase and helicase domain in one molecule<ref name="Zahn">PMID:2577526</ref>. Crystal structures have been solved for the apo form of the [http://www.rcsb.org/structure/5a9j helicase-like domain] and the ternary complex of the [http://http://www.rcsb.org/structure/4X0P polymerase domain]. The focus of this wiki is the polymerase domain.
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Pol θ is thought to promote overall genomic stability by performing several distinct cellular functions. The primary role of the enzyme is to repair of double-stranded DNA breaks as the key enzyme in an error-prone non-homologous end-joining pathway called alternative end-joining (6) or theta-mediated end-joining. Other functions include translesion synthesis, the ability of the polymerase to bypass and extend past a site of oxidative DNA damage (7), base excision repair (8), and possibly DNA replication timing (9). Pol θ has the specialized ability to extend DNA from minimally-paired primers (termed microhomologous){{cn}}. Repair by this enzyme is considered to error-prone due to its tendency to add or delete short indels (6).
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Pol θ is thought to promote overall genomic stability by performing several distinct cellular functions. The primary role of the enzyme is to repair of double-stranded DNA breaks as the key enzyme in an error-prone non-homologous end-joining pathway called alternative end-joining<ref name="Instability">PubMed:25275444</ref> or theta-mediated end-joining. Other functions include translesion synthesis, the ability of the polymerase to bypass and extend past a site of oxidative DNA damage<ref>PubMed:24648516</ref>, base excision repair <ref>PubMed:21917855</ref>, and possibly DNA replication timing <ref>PubMed:24989122</ref>. Pol θ has the specialized ability to extend DNA from minimally-paired primers (termed microhomologous){{cn}}. Repair by this enzyme is considered to error-prone due to its tendency to add or delete short indels <ref name="Instability" />.
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Several types of cancer, such as breast, ovarian, and oral carcinomas, have shown significantly higher expression levels of pol θ and linked to poorer patient outcomes (10,11,12). Genomic studies have shown that more than half of epithelial ovarian cancers have defects in the error-free repair pathway of homologous recombination (13) and, as a result, have an increased dependence on theta-mediated end-joining (10). Double-stranded break repair by pol θ may be thought of as a "backup" pathway which cells depend on more when the machinery involved in homologous recombination is compromised or otherwise unavailable. This enzyme has been identified as a potential therapeutic target due to overexpression in cancers in combination with studies that have shown inhibition of pol θ to sensitize human and mouse cells to radiation and chemical agents which induce double-stranded breaks (10,14,15)
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Several types of cancer, such as breast, ovarian, and oral carcinomas, have shown significantly higher expression levels of pol θ and correlate to poorer patient outcomes<ref name="Ceccaldi">PMID:25642963</ref><ref>PubMed:20624954</ref><ref>PubMed:22987617</ref>. Genomic studies have shown that more than half of epithelial ovarian cancers have defects in the error-free repair pathway of homologous recombination<ref>PMID:21720365</ref> and, as a result, have an increased dependence on theta-mediated end-joining <ref name="Ceccaldi" />. Double-stranded break repair by pol θ may be thought of as a "backup" pathway which cells depend on more when the machinery involved in homologous recombination is compromised or otherwise unavailable. This enzyme has been identified as a potential therapeutic target due to overexpression in cancers in combination with studies that have shown inhibition of pol θ to sensitize human and mouse cells to radiation and chemical agents which induce double-stranded breaks<ref name="Ceccaldi" /><ref>PubMed:19630521</ref><ref>PubMed:20233878</ref>.

Revision as of 18:33, 28 April 2018

DNA Polymerase θ

PDB ID 4x0p

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References

1. Yousefzadeh MJ, Wood RD. DNA polymerase POLQ and cellular defense against DNA damage. DNA Repair (Amst). 2013; 12:1–9. [PubMed: 23219161] 2. Seki M, Marini F, Wood RD. POLQ (Pol theta), a DNA polymerase and DNA-dependent ATPase in human cells. Nucleic Acids Res. 2003; 31:6117–6126. [PubMed: 14576298] 3. Sfeir RPA 4. Pomerantz Helicase PMID:29444826 5. Zahn 6. Newman 6. Yousefzadeh MJ, et al. Mechanism of Suppression of Chromosomal Instability by DNA Polymerase POLQ. PLoS Genet. 2014; 10:e1004654. [PubMed: 25275444] 7. Yoon JH, Roy Choudhury J, Park J, Prakash S, Prakash L. A role for DNA polymerase theta in promoting replication through oxidative DNA lesion, thymine glycol, in human cells. J Biol Chem. 2014; 289:13177–13185. [PubMed: 24648516] 8. Asagoshi K, et al. Single-nucleotide base excision repair DNA polymerase activity in C. elegans in the absence of DNA polymerase beta. Nucleic Acids Res. 2012; 40:670–681. [PubMed: 21917855] 9. Fernandez-Vidal A, et al. A role for DNA polymerase theta in the timing of DNA replication. Nat Commun. 2014; 5:4285. [PubMed: 24989122] 10. Ceccaldi 11. Lemee F, et al. DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability. Proc Natl Acad Sci U S A. 2010; 107:13390–13395. [PubMed: 20624954] 12. Lessa RC, et al. Identification of upregulated genes in oral squamous cell carcinomas. Head Neck. 2013; 35:1475–1481. [PubMed: 22987617] 13. Cancer Genome Atlas Research, N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474:609–615.10.1038/nature10166 14. Goff JP, et al. Lack of DNA polymerase theta (POLQ) radiosensitizes bone marrow stromal cells in vitro and increases reticulocyte micronuclei after total-body irradiation. Radiat Res. 2009; 172:165–174. [PubMed: 19630521] 15. Higgins GS, et al. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Cancer Res. 2010; 70:2984–2993. [PubMed: 20233878]

  1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
  3. ↑ Yousefzadeh MJ, Wood RD. DNA polymerase POLQ and cellular defense against DNA damage. DNA Repair (Amst). 2013 Jan 1;12(1):1-9. doi: 10.1016/j.dnarep.2012.10.004. Epub , 2012 Dec 4. PMID:23219161 doi:http://dx.doi.org/10.1016/j.dnarep.2012.10.004
  4. ↑ 4.0 4.1 Seki M, Marini F, Wood RD. POLQ (Pol theta), a DNA polymerase and DNA-dependent ATPase in human cells. Nucleic Acids Res. 2003 Nov 1;31(21):6117-26. PMID:14576298
  5. ↑ Mateos-Gomez PA, Kent T, Deng SK, McDevitt S, Kashkina E, Hoang TM, Pomerantz RT, Sfeir A. The helicase domain of Poltheta counteracts RPA to promote alt-NHEJ. Nat Struct Mol Biol. 2017 Dec;24(12):1116-1123. doi: 10.1038/nsmb.3494. Epub 2017, Oct 23. PMID:29058711 doi:http://dx.doi.org/10.1038/nsmb.3494
  6. ↑ Ozdemir AY, Rusanov T, Kent T, Siddique LA, Pomerantz RT. Polymerase theta-helicase efficiently unwinds DNA and RNA-DNA hybrids. J Biol Chem. 2018 Apr 6;293(14):5259-5269. doi: 10.1074/jbc.RA117.000565. Epub, 2018 Feb 14. PMID:29444826 doi:http://dx.doi.org/10.1074/jbc.RA117.000565
  7. ↑ Nussbaum J, Zane EA, Thys DM. Esmolol for the treatment of hypercyanotic spells in infants with tetralogy of Fallot. J Cardiothorac Anesth. 1989 Apr;3(2):200-2. PMID:2577526
  8. ↑ 8.0 8.1 PubMed:25275444
  9. ↑ PubMed:24648516
  10. ↑ PubMed:21917855
  11. ↑ PubMed:24989122
  12. ↑ 12.0 12.1 12.2 Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, O'Connor KW, Konstantinopoulos PA, Elledge SJ, Boulton SJ, Yusufzai T, D'Andrea AD. Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature. 2015 Feb 12;518(7538):258-62. doi: 10.1038/nature14184. Epub 2015 Feb 2. PMID:25642963 doi:http://dx.doi.org/10.1038/nature14184
  13. ↑ PubMed:20624954
  14. ↑ PubMed:22987617
  15. ↑ . Integrated genomic analyses of ovarian carcinoma. Nature. 2011 Jun 29;474(7353):609-15. doi: 10.1038/nature10166. PMID:21720365 doi:http://dx.doi.org/10.1038/nature10166
  16. ↑ PubMed:19630521
  17. ↑ PubMed:20233878

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Scott H. Vanson

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