Editing Reverse transcriptase (section)

== Replication fidelity ==

There are three different replication systems during the life cycle of a retrovirus. The first process is the reverse transcriptase synthesis of viral DNA from viral RNA, which then forms newly made complementary DNA strands. The second replication process occurs when host cellular DNA polymerase replicates the integrated viral DNA. Lastly, RNA polymerase II transcribes the proviral DNA into RNA, which will be packed into virions. Mutation can occur during one or all of these replication steps.<ref>{{cite book |vauthors = Bbenek K, Kunkel AT| veditors = Skalka MA, Goff PS | title = Reverse transcriptase | publisher = Cold Spring Harbor Laboratory Press | location = New York | year = 1993 | chapter = The fidelity of retroviral reverse transcriptases | page = 85 | isbn = 978-0-87969-382-4 }}</ref>

Reverse transcriptase has a high error rate when transcribing RNA into DNA since, unlike most other [[DNA polymerase]]s, it has no [[Proofreading (biology)|proofreading]] ability. This high error rate allows [[mutation]]s to accumulate at an accelerated rate relative to proofread forms of replication. The commercially available reverse transcriptases produced by [[Promega]] are quoted by their manuals as having error rates in the range of 1 in 17,000 bases for AMV and 1 in 30,000 bases for M-MLV.<ref>{{cite web | url = http://www.promega.com/pnotes/71/7807_22/7807_22_core.pdf | title = Promega kit instruction manual | date = 1999 | archive-url = https://web.archive.org/web/20061121205121/http://www.promega.com/pnotes/71/7807_22/7807_22_core.pdf | archive-date = 2006-11-21 | url-status = dead }}</ref>

Other than creating [[single-nucleotide polymorphism]]s, reverse transcriptases have also been shown to be involved in processes such as [[transcript fusion]]s, [[exon shuffling]] and creating artificial [[antisense]] transcripts.<ref name="pmid20805885">{{cite journal | vauthors = Houseley J, Tollervey D | title = Apparent non-canonical trans-splicing is generated by reverse transcriptase in vitro | journal = PLOS ONE | volume = 5 | issue = 8 | pages = e12271 | date = August 2010 | pmid = 20805885 | pmc = 2923612 | doi = 10.1371/journal.pone.0012271 | bibcode = 2010PLoSO...512271H | doi-access = free }}</ref><ref name="pmid12044895">{{cite journal | vauthors = Zeng XC, Wang SX | title = Evidence that BmTXK beta-BmKCT cDNA from Chinese scorpion Buthus martensii Karsch is an artifact generated in the reverse transcription process | journal = FEBS Letters | volume = 520 | issue = 1–3 | pages = 183–4; author reply 185 | date = June 2002 | pmid = 12044895 | doi = 10.1016/S0014-5793(02)02812-0 | s2cid = 24619868 | doi-access = free }}</ref> It has been speculated that this ''template switching'' activity of reverse transcriptase, which can be demonstrated completely ''in vivo'', may have been one of the causes for finding several thousand unannotated transcripts in the genomes of model organisms.<ref>{{cite journal | title = Response to "The Reality of Pervasive Transcription" | year = 2011  |vauthors = van Bakel H, Nislow C, Blencowe BJ, Hughes TR | journal = PLOS Biology | volume = 9 | issue = 7 | pages = e1001102 | doi = 10.1371/journal.pbio.1001102 | pmc = 3134445 | doi-access = free }}</ref>

===Template switching===

Two [[RNA]] [[genome]]s are packaged into each retrovirus particle, but, after an infection, each virus generates only one [[provirus]].<ref name = Rawson2018>{{cite journal | vauthors = Rawson JM, Nikolaitchik OA, Keele BF, Pathak VK, Hu WS | title = Recombination is required for efficient HIV-1 replication and the maintenance of viral genome integrity | journal = Nucleic Acids Research | volume = 46 | issue = 20 | pages = 10535–10545 | date = November 2018 | pmid = 30307534 | pmc = 6237782 | doi = 10.1093/nar/gky910 }}</ref>  After infection, reverse transcription is accompanied by template switching between the two genome copies (copy choice recombination).<ref name = Rawson2018/>  There are two models that suggest why RNA transcriptase switches templates. The first, the forced copy-choice model, proposes that reverse transcriptase changes the RNA template when it encounters a nick, implying that recombination is obligatory to maintaining virus genome integrity. The second, the dynamic choice model, suggests that reverse transcriptase changes templates when the RNAse function and the polymerase function are not in sync rate-wise, implying that recombination occurs at random and is not in response to genomic damage. A study by Rawson et al. supported both models of recombination.<ref name = Rawson2018 /> From 5 to 14 recombination events per genome occur at each replication cycle.<ref name="pmid26691546">{{cite journal | vauthors = Cromer D, Grimm AJ, Schlub TE, Mak J, Davenport MP | title = Estimating the in-vivo HIV template switching and recombination rate | journal = AIDS | volume = 30 | issue = 2 | pages = 185–92 | date = January 2016 | pmid = 26691546 | doi = 10.1097/QAD.0000000000000936 | s2cid = 20086739 | doi-access = free }}</ref>  Template switching (recombination) appears to be necessary for maintaining genome integrity and as a repair mechanism for salvaging damaged genomes.<ref name="pmid1700865">{{cite journal | vauthors = Hu WS, Temin HM | title = Retroviral recombination and reverse transcription | journal = Science | location = New York, N.Y. | volume = 250 | issue = 4985 | pages = 1227–33 | date = November 1990 | pmid = 1700865 | doi = 10.1126/science.1700865 | bibcode = 1990Sci...250.1227H }}</ref><ref name="Rawson2018" />