POLQ
{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
DNA polymerase theta is an enzyme that in humans is encoded by the POLQ gene.{{cite journal | vauthors = Sharief FS, Vojta PJ, Ropp PA, Copeland WC | title = Cloning and chromosomal mapping of the human DNA polymerase theta (POLQ), the eighth human DNA polymerase | journal = Genomics | volume = 59 | issue = 1 | pages = 90–6 | date = July 1999 | pmid = 10395804 | doi = 10.1006/geno.1999.5843 }}{{cite web | title = Entrez Gene: POLQ polymerase (DNA directed), theta| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10721}} This polymerase plays a key role in one of the three major double strand break repair pathways: theta-mediated end joining (TMEJ).{{cite journal | vauthors = Chan SH, Yu AM, McVey M | title = Dual roles for DNA polymerase theta in alternative end-joining repair of double-strand breaks in Drosophila | journal = PLOS Genetics | volume = 6 | issue = 7 | pages = e1001005 | date = July 2010 | pmid = 20617203 | pmc = 2895639 | doi = 10.1371/journal.pgen.1001005 | doi-access = free }}{{cite journal | vauthors = Yu AM, McVey M | title = Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions | journal = Nucleic Acids Research | volume = 38 | issue = 17 | pages = 5706–17 | date = September 2010 | pmid = 20460465 | pmc = 2943611 | doi = 10.1093/nar/gkq379 | url = }}{{cite journal | vauthors = Koole W, van Schendel R, Karambelas AE, van Heteren JT, Okihara KL, Tijsterman M | title = A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites | journal = Nature Communications | volume = 5 | issue = 1 | pages = 3216 | date = 2014-02-05 | pmid = 24496117 | doi = 10.1038/ncomms4216 | bibcode = 2014NatCo...5.3216K | doi-access = free }}{{cite journal | vauthors = Roerink SF, van Schendel R, Tijsterman M | title = Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans | journal = Genome Research | volume = 24 | issue = 6 | pages = 954–62 | date = June 2014 | pmid = 24614976 | pmc = 4032859 | doi = 10.1101/gr.170431.113 }} Most double-strand breaks are repaired by non-homologous end joining (NHEJ) or homology directed repair (HDR). However, in some contexts, NHEJ and HR are insufficient and TMEJ is the only solution to repair the break.{{cite journal | vauthors = Schimmel J, van Schendel R, den Dunnen JT, Tijsterman M | title = Templated Insertions: A Smoking Gun for Polymerase Theta-Mediated End Joining | journal = Trends in Genetics | volume = 35 | issue = 9 | pages = 632–644 | date = September 2019 | pmid = 31296341 | doi = 10.1016/j.tig.2019.06.001 | s2cid = 195892718 }} TMEJ is often described as alternative NHEJ, but differs in that it lacks a requirement for the Ku heterodimer, and it can only act on resected DNA ends.{{cite journal | vauthors = Yousefzadeh MJ, Wyatt DW, Takata K, Mu Y, Hensley SC, Tomida J, Bylund GO, Doublié S, Johansson E, Ramsden DA, McBride KM, Wood RD | display-authors = 6 | title = Mechanism of suppression of chromosomal instability by DNA polymerase POLQ | journal = PLOS Genetics | volume = 10 | issue = 10 | pages = e1004654 | date = October 2014 | pmid = 25275444 | pmc = 4183433 | doi = 10.1371/journal.pgen.1004654 | doi-access = free }} Following annealing of short (i.e., a few nucleotides) regions on the DNA overhangs, DNA polymerase theta catalyzes template-dependent DNA synthesis across the broken ends, stabilizing the paired structure.{{cite journal | vauthors = Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A | title = Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination | journal = Nature | volume = 518 | issue = 7538 | pages = 254–7 | date = February 2015 | pmid = 25642960 | pmc = 4718306 | doi = 10.1038/nature14157 | bibcode = 2015Natur.518..254M }}{{cite journal | vauthors = 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 | display-authors = 6 | title = Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair | journal = Nature | volume = 518 | issue = 7538 | pages = 258–62 | date = February 2015 | pmid = 25642963 | pmc = 4415602 | doi = 10.1038/nature14184 | bibcode = 2015Natur.518..258C }}
Polymerase theta's mutational signature
TMEJ is intrinsically mutagenic, since polymerase theta uses homologous nucleotides from both break ends to initiate repair, which leads to loss of one set of these nucleotides in the DNA sequence. Therefore, TMEJ is a form of micro-homology mediated end joining (MMEJ). Moreover, when break ends are not stabilized properly, the break ends can detach after polymerization. When these polymerized ends anneal again, a templated insert arises between the deletion junctions.{{cite journal | vauthors = Schimmel J, van Schendel R, den Dunnen JT, Tijsterman M | title = Templated Insertions: A Smoking Gun for Polymerase Theta-Mediated End Joining | journal = Trends in Genetics | volume = 35 | issue = 9 | pages = 632–644 | date = September 2019 | pmid = 31296341 | doi = 10.1016/j.tig.2019.06.001 | s2cid = 195892718 }}
Reverse transcription of RNA
Polθ promotes RNA-templated DNA repair. Previously, DNA polymerases were long thought to only transcribe DNA into DNA or RNA and not be able to write RNA segments into DNA.{{cite news |title=New discovery shows human cells can write RNA sequences into DNA |url=https://phys.org/news/2021-06-discovery-human-cells-rna-sequences.html |access-date=10 July 2021 |work=phys.org |language=en}}{{cite journal | vauthors = Chandramouly G, Zhao J, McDevitt S, Rusanov T, Hoang T, Borisonnik N, Treddinick T, Lopezcolorado FW, Kent T, Siddique LA, Mallon J, Huhn J, Shoda Z, Kashkina E, Brambati A, Stark JM, Chen XS, Pomerantz RT | display-authors = 6 | title = Polθ reverse transcribes RNA and promotes RNA-templated DNA repair | journal = Science Advances | volume = 7 | issue = 24 | pages = eabf1771 | date = June 2021 | pmid = 34117057 | pmc = 8195485 | doi = 10.1126/sciadv.abf1771 | bibcode = 2021SciA....7.1771C }}
References
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Further reading
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- {{cite journal | vauthors = Hogg M, Sauer-Eriksson AE, Johansson E | title = Promiscuous DNA synthesis by human DNA polymerase θ | journal = Nucleic Acids Research | volume = 40 | issue = 6 | pages = 2611–22 | date = March 2012 | pmid = 22135286 | pmc = 3315306 | doi = 10.1093/nar/gkr1102 }}
- {{cite journal | vauthors = Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC | title = Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening | journal = Genomics | volume = 23 | issue = 1 | pages = 42–50 | date = September 1994 | pmid = 7829101 | doi = 10.1006/geno.1994.1457 }}
- {{cite journal | vauthors = Maga G, Shevelev I, Ramadan K, Spadari S, Hübscher U | title = DNA polymerase theta purified from human cells is a high-fidelity enzyme | journal = Journal of Molecular Biology | volume = 319 | issue = 2 | pages = 359–69 | date = May 2002 | pmid = 12051913 | doi = 10.1016/S0022-2836(02)00325-X }}
- {{cite journal | vauthors = Seki M, Marini F, Wood RD | title = POLQ (Pol theta), a DNA polymerase and DNA-dependent ATPase in human cells | journal = Nucleic Acids Research | volume = 31 | issue = 21 | pages = 6117–26 | date = November 2003 | pmid = 14576298 | pmc = 275456 | doi = 10.1093/nar/gkg814 }}
- {{cite journal | vauthors = Kawamura K, Bahar R, Seimiya M, Chiyo M, Wada A, Okada S, Hatano M, Tokuhisa T, Kimura H, Watanabe S, Honda I, Sakiyama S, Tagawa M, O-Wang J | display-authors = 6 | title = DNA polymerase theta is preferentially expressed in lymphoid tissues and upregulated in human cancers | journal = International Journal of Cancer | volume = 109 | issue = 1 | pages = 9–16 | date = March 2004 | pmid = 14735462 | doi = 10.1002/ijc.11666 | s2cid = 19912440 | doi-access = }}
- {{cite journal | vauthors = Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S | display-authors = 6 | title = Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions | journal = Genome Research | volume = 14 | issue = 9 | pages = 1711–8 | date = September 2004 | pmid = 15342556 | pmc = 515316 | doi = 10.1101/gr.2435604 }}
- {{cite journal | vauthors = Seki M, Masutani C, Yang LW, Schuffert A, Iwai S, Bahar I, Wood RD | title = High-efficiency bypass of DNA damage by human DNA polymerase Q | journal = The EMBO Journal | volume = 23 | issue = 22 | pages = 4484–94 | date = November 2004 | pmid = 15496986 | pmc = 526458 | doi = 10.1038/sj.emboj.7600424 }}
- {{cite journal | vauthors = Chiapperino D, Cai M, Sayer JM, Yagi H, Kroth H, Masutani C, Hanaoka F, Jerina DM, Cheh AM | display-authors = 6 | title = Error-prone translesion synthesis by human DNA polymerase eta on DNA-containing deoxyadenosine adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene | journal = The Journal of Biological Chemistry | volume = 280 | issue = 48 | pages = 39684–92 | date = December 2005 | pmid = 16188888 | doi = 10.1074/jbc.M508008200 | doi-access = free }}
- {{cite journal | vauthors = Zan H, Shima N, Xu Z, Al-Qahtani A, Evinger Iii AJ, Zhong Y, Schimenti JC, Casali P | display-authors = 6 | title = The translesion DNA polymerase theta plays a dominant role in immunoglobulin gene somatic hypermutation | journal = The EMBO Journal | volume = 24 | issue = 21 | pages = 3757–69 | date = November 2005 | pmid = 16222339 | pmc = 1276717 | doi = 10.1038/sj.emboj.7600833 }}
- {{cite journal | vauthors = Cruet-Hennequart S, Coyne S, Glynn MT, Oakley GG, Carty MP | title = UV-induced RPA phosphorylation is increased in the absence of DNA polymerase eta and requires DNA-PK | journal = DNA Repair | volume = 5 | issue = 4 | pages = 491–504 | date = April 2006 | pmid = 16520097 | doi = 10.1016/j.dnarep.2006.01.008 }}
- {{cite journal | vauthors = Chen YW, Cleaver JE, Hanaoka F, Chang CF, Chou KM | title = A novel role of DNA polymerase eta in modulating cellular sensitivity to chemotherapeutic agents | journal = Molecular Cancer Research | volume = 4 | issue = 4 | pages = 257–65 | date = April 2006 | pmid = 16603639 | doi = 10.1158/1541-7786.MCR-05-0118 | doi-access = free }}
- {{cite journal | vauthors = Yuasa MS, Masutani C, Hirano A, Cohn MA, Yamaizumi M, Nakatani Y, Hanaoka F | title = A human DNA polymerase eta complex containing Rad18, Rad6 and Rev1; proteomic analysis and targeting of the complex to the chromatin-bound fraction of cells undergoing replication fork arrest | journal = Genes to Cells | volume = 11 | issue = 7 | pages = 731–44 | date = July 2006 | pmid = 16824193 | doi = 10.1111/j.1365-2443.2006.00974.x | s2cid = 32695133 | doi-access = }}
- {{cite journal | vauthors = Choi JY, Stover JS, Angel KC, Chowdhury G, Rizzo CJ, Guengerich FP | title = Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens: Human DNA polymerase eta selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site | journal = The Journal of Biological Chemistry | volume = 281 | issue = 35 | pages = 25297–306 | date = September 2006 | pmid = 16835218 | doi = 10.1074/jbc.M605699200 | doi-access = free }}
- {{cite journal | vauthors = Kino K, Ito N, Sugasawa K, Sugiyama H, Hanaoka F | title = Translesion synthesis by human DNA polymerase eta across oxidative products of guanine | journal = Nucleic Acids Symposium Series | volume = 48 | issue = 48 | pages = 171–2 | year = 2007 | pmid = 17150533 | doi = 10.1093/nass/48.1.171 | doi-access = free }}
- {{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | display-authors = 6 | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Molecular Systems Biology | volume = 3 | issue = 1 | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}
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