DNA polymerase theta is an enzyme that in humans is encoded by the POLQgene.[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]
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.[15]
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.[16][17]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. PMID10395804.
^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. PMID31296341. S2CID195892718.
^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. PMID31296341. S2CID195892718.
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Maga G, Shevelev I, Ramadan K, Spadari S, Hübscher U (May 2002). "DNA polymerase theta purified from human cells is a high-fidelity enzyme". Journal of Molecular Biology. 319 (2): 359–69. doi:10.1016/S0022-2836(02)00325-X. PMID12051913.
Kawamura K, Bahar R, Seimiya M, Chiyo M, Wada A, Okada S, et al. (March 2004). "DNA polymerase theta is preferentially expressed in lymphoid tissues and upregulated in human cancers". International Journal of Cancer. 109 (1): 9–16. doi:10.1002/ijc.11666. PMID14735462. S2CID19912440.
Cruet-Hennequart S, Coyne S, Glynn MT, Oakley GG, Carty MP (April 2006). "UV-induced RPA phosphorylation is increased in the absence of DNA polymerase eta and requires DNA-PK". DNA Repair. 5 (4): 491–504. doi:10.1016/j.dnarep.2006.01.008. PMID16520097.
Yuasa MS, Masutani C, Hirano A, Cohn MA, Yamaizumi M, Nakatani Y, Hanaoka F (July 2006). "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". Genes to Cells. 11 (7): 731–44. doi:10.1111/j.1365-2443.2006.00974.x. PMID16824193. S2CID32695133.
