DNA polymerase theta is an enzyme that in humans is encoded by the POLQ gene.[5][6] This polymerase plays a key role in one of the three major double strand break repair pathways: theta-mediated end joining (TMEJ).[7][8][9][10] 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.[11] 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.[12] 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.[13][14]

POLQ
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPOLQ, POLH, PRO0327, polymerase (DNA) theta, DNA polymerase theta, DNA polymerase θ
External IDsOMIM: 604419; MGI: 2155399; HomoloGene: 32727; GeneCards: POLQ; OMA:POLQ - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_199420
NM_006596

NM_001159369
NM_029977

RefSeq (protein)

NP_955452

NP_001152841
NP_084253

Location (UCSC)Chr 3: 121.43 – 121.55 MbChr 16: 36.83 – 36.92 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Polymerase theta's mutational signature

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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.[15]

Reverse transcription of RNA

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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.[16][17]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000051341Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034206Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Sharief FS, Vojta PJ, Ropp PA, Copeland WC (July 1999). "Cloning and chromosomal mapping of the human DNA polymerase theta (POLQ), the eighth human DNA polymerase". Genomics. 59 (1): 90–6. doi:10.1006/geno.1999.5843. PMID 10395804.
  6. ^ "Entrez Gene: POLQ polymerase (DNA directed), theta".
  7. ^ Chan SH, Yu AM, McVey M (July 2010). "Dual roles for DNA polymerase theta in alternative end-joining repair of double-strand breaks in Drosophila". PLOS Genetics. 6 (7): e1001005. doi:10.1371/journal.pgen.1001005. PMC 2895639. PMID 20617203.
  8. ^ Yu AM, McVey M (September 2010). "Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions". Nucleic Acids Research. 38 (17): 5706–17. doi:10.1093/nar/gkq379. PMC 2943611. PMID 20460465.
  9. ^ Koole W, van Schendel R, Karambelas AE, van Heteren JT, Okihara KL, Tijsterman M (2014-02-05). "A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites". Nature Communications. 5 (1): 3216. Bibcode:2014NatCo...5.3216K. doi:10.1038/ncomms4216. PMID 24496117.
  10. ^ Roerink SF, van Schendel R, Tijsterman M (June 2014). "Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans". Genome Research. 24 (6): 954–62. doi:10.1101/gr.170431.113. PMC 4032859. PMID 24614976.
  11. ^ Schimmel J, van Schendel R, den Dunnen JT, Tijsterman M (September 2019). "Templated Insertions: A Smoking Gun for Polymerase Theta-Mediated End Joining". Trends in Genetics. 35 (9): 632–644. doi:10.1016/j.tig.2019.06.001. PMID 31296341. S2CID 195892718.
  12. ^ Yousefzadeh MJ, Wyatt DW, Takata K, Mu Y, Hensley SC, Tomida J, et al. (October 2014). "Mechanism of suppression of chromosomal instability by DNA polymerase POLQ". PLOS Genetics. 10 (10): e1004654. doi:10.1371/journal.pgen.1004654. PMC 4183433. PMID 25275444.
  13. ^ Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A (February 2015). "Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination". Nature. 518 (7538): 254–7. Bibcode:2015Natur.518..254M. doi:10.1038/nature14157. PMC 4718306. PMID 25642960.
  14. ^ Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, et al. (February 2015). "Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair". Nature. 518 (7538): 258–62. Bibcode:2015Natur.518..258C. doi:10.1038/nature14184. PMC 4415602. PMID 25642963.
  15. ^ Schimmel J, van Schendel R, den Dunnen JT, Tijsterman M (September 2019). "Templated Insertions: A Smoking Gun for Polymerase Theta-Mediated End Joining". Trends in Genetics. 35 (9): 632–644. doi:10.1016/j.tig.2019.06.001. PMID 31296341. S2CID 195892718.
  16. ^ "New discovery shows human cells can write RNA sequences into DNA". phys.org. Retrieved 10 July 2021.
  17. ^ Chandramouly G, Zhao J, McDevitt S, Rusanov T, Hoang T, Borisonnik N, et al. (June 2021). "Polθ reverse transcribes RNA and promotes RNA-templated DNA repair". Science Advances. 7 (24): eabf1771. Bibcode:2021SciA....7.1771C. doi:10.1126/sciadv.abf1771. PMC 8195485. PMID 34117057.

Further reading

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