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RecA

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recA bacterial DNA recombination protein
Crystal structure of a RecA-DNA complex. PDB ID: 3cmt.[1]
Identifiers
SymbolRecA
PfamPF00154
Pfam clanCL0023
InterProIPR013765
PROSITEPDOC00131
SCOP22reb / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

RecA is a 38 kilodalton protein essential for the repair and maintenance of DNA in bacteria.[2] Structural and functional homologs to RecA have been found in all kingdoms of life.[3][4] RecA serves as an archetype for this class of homologous DNA repair proteins. The homologous protein is called RAD51 in eukaryotes and RadA in archaea.[5][6]

RecA has multiple activities, all related to DNA repair. In the bacterial SOS response, it has a co-protease[7] function in the autocatalytic cleavage of the LexA repressor and the λ repressor.[8]

Function

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Homologous recombination

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The RecA protein binds strongly and in long clusters to ssDNA to form a nucleoprotein filament.[9] The protein has more than one DNA binding site, and thus can hold a single strand and double strand together. This feature makes it possible to catalyze a DNA synapsis reaction between a DNA double helix and a complementary region of single-stranded DNA. The RecA-ssDNA filament searches for sequence similarity along the dsDNA. A disordered DNA loop in RecA, Loop 2, contains the residues responsible for DNA homologous recombination.[10] In some bacteria, RecA posttranslational modification via phosphorylation of a serine residue on Loop 2 can interfere with homologous recombination.[11]

There are multiple proposed models for how RecA finds complementary DNA.[9] In one model, termed conformational proofreading, the DNA duplex is stretched, which enhances sequence complementarity recognition.[12][13] The reaction initiates the exchange of strands between two recombining DNA double helices. After the synapsis event, in the heteroduplex region a process called branch migration begins. In branch migration an unpaired region of one of the single strands displaces a paired region of the other single strand, moving the branch point without changing the total number of base pairs. Spontaneous branch migration can occur, however, as it generally proceeds equally in both directions it is unlikely to complete recombination efficiently. The RecA protein catalyzes unidirectional branch migration and by doing so makes it possible to complete recombination, producing a region of heteroduplex DNA that is thousands of base pairs long.

Since it is a DNA-dependent ATPase, RecA contains an additional site for binding and hydrolyzing ATP. RecA associates more tightly with DNA when it has ATP bound than when it has ADP bound.[14]

In Escherichia coli, homologous recombination events mediated by RecA can occur during the period after DNA replication when sister loci remain close. RecA can also mediate homology pairing, homologous recombination and DNA break repair between distant sister loci that had segregated to opposite halves of the E. coli cell.[15]

Natural transformation

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Main article: Natural competence

Natural bacterial transformation involves the transfer of DNA from one bacterium to another (ordinarily of the same species) and the integration of the donor DNA into the recipient chromosome by homologous recombination, a process mediated by the RecA protein. In some bacteria, the recA gene is induced in response to the bacterium becoming competent, the physiological state required for transformation.[16] In Bacillus subtilis the length of the transferred DNA can be as great as a third and up to the size of the whole chromosome.[17][18]

Clinical significance

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RecA has been proposed as a potential drug target for bacterial infections.[19] Small molecules that interfere with RecA function have been identified.[20][21] Since many antibiotics lead to DNA damage, and all bacteria rely on RecA to fix this damage, inhibitors of RecA could be used to enhance the toxicity of antibiotics. Inhibitors of RecA may also delay or prevent the appearance of bacterial drug resistance.[19]

References

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  1. ^ Chen, Z.; Yang, H.; Pavletich, N. P. (2008). "Mechanism of homologous recombination from the RecA–ssDNA/dsDNA structures". Nature. 453 (7194): 489–4. Bibcode:2008Natur.453..489C. doi:10.1038/nature06971. PMID 18497818. S2CID 4416531.
  2. ^ Horii, T; Ogawa, T; Ogawa, H (January 1980). "Organization of the recA gene of Escherichia coli". Proceedings of the National Academy of Sciences. 77 (1): 313–317. Bibcode:1980PNAS...77..313H. doi:10.1073/pnas.77.1.313. PMC 348260. PMID 6244554.
  3. ^ Lin, Zhenguo; Kong, Hongzhi; Nei, Masatoshi; Ma, Hong (5 July 2006). "Origins and evolution of the recA / RAD51 gene family: Evidence for ancient gene duplication and endosymbiotic gene transfer". Proceedings of the National Academy of Sciences. 103 (27): 10328–10333. Bibcode:2006PNAS..10310328L. doi:10.1073/pnas.0604232103. PMC 1502457. PMID 16798872.
  4. ^ Brendel, Volker; Brocchieri, Luciano; Sandler, Steven J.; Clark, Alvin J.; Karlin, Samuel (May 1997). "Evolutionary Comparisons of RecA-Like Proteins Across All Major Kingdoms of Living Organisms". Journal of Molecular Evolution. 44 (5): 528–541. doi:10.1007/pl00006177. PMID 9115177.
  5. ^ Shinohara, Akira; Ogawa, Hideyuki; Ogawa, Tomoko (1992). "Rad51 protein involved in repair and recombination in S. cerevisiae is a RecA-like protein". Cell. 69 (3): 457–470. doi:10.1016/0092-8674(92)90447-k. PMID 1581961. S2CID 35937283.
  6. ^ Seitz, Erica M.; Brockman, Joel P.; Sandler, Steven J.; Clark, A. John; Kowalczykowski, Stephen C. (1998-05-01). "RadA protein is an archaeal RecA protein homolog that catalyzes DNA strand exchange". Genes & Development. 12 (9): 1248–1253. doi:10.1101/gad.12.9.1248. ISSN 0890-9369. PMC 316774. PMID 9573041.
  7. ^ Horii, Toshihiro; Ogawa, Tomoko; Nakatani, Tomoyuki; Hase, Toshiharu; Matsubara, Hiroshi; Ogawa, Hideyuki (December 1981). "Regulation of SOS functions: Purification of E. coli LexA protein and determination of its specific site cleaved by the RecA protein". Cell. 27 (3): 515–522. doi:10.1016/0092-8674(81)90393-7. PMID 6101204. S2CID 45482725.
  8. ^ Little, JW (March 1984). "Autodigestion of lexA and phage lambda repressors". Proceedings of the National Academy of Sciences. 81 (5): 1375–1379. Bibcode:1984PNAS...81.1375L. doi:10.1073/pnas.81.5.1375. PMC 344836. PMID 6231641.
  9. ^ a b Henkin, Tina M.; Peters, Joseph E.; Snyder, Larry; Champness, Wendy (2020). Snyder & Champness molecular genetics of bacteria (Fifth ed.). Hoboken, NJ: Wiley. pp. 368–371. ISBN 9781555819750.
  10. ^ Maraboeuf, Fabrice; Voloshin, Oleg; Camerini-Otero, R. Daniel; Takahashi, Masayuki (December 1995). "The Central Aromatic Residue in Loop L2 of RecA Interacts with DNA". Journal of Biological Chemistry. 270 (52): 30927–30932. doi:10.1074/jbc.270.52.30927. PMID 8537348.
  11. ^ Wipperman, Matthew F.; Heaton, Brook E.; Nautiyal, Astha; Adefisayo, Oyindamola; Evans, Henry; Gupta, Richa; van Ditmarsch, Dave; Soni, Rajesh; Hendrickson, Ron; Johnson, Jeff; Krogan, Nevan; Glickman, Michael S. (October 2018). "Mycobacterial Mutagenesis and Drug Resistance Are Controlled by Phosphorylation- and Cardiolipin-Mediated Inhibition of the RecA Coprotease". Molecular Cell. 72 (1): 152–161.e7. doi:10.1016/j.molcel.2018.07.037. PMC 6389330. PMID 30174294.
  12. ^ Savir, Yonatan; Tlusty, Tsvi (November 2010). "RecA-Mediated Homology Search as a Nearly Optimal Signal Detection System". Molecular Cell. 40 (3): 388–396. arXiv:1011.4382. doi:10.1016/j.molcel.2010.10.020. PMID 21070965. S2CID 1682936.
  13. ^ De Vlaminck, Iwijn; van Loenhout, Marjin T.J.; Zweifel, Ludovit; den Blanken, Johan; Hooning, Koen; Hage, Susanne; Kerssemakers, Jacob; Dekker, Cees (June 2012). "Mechanism of Homology Recognition in DNA Recombination from Dual-Molecule Experiments". Molecular Cell. 46 (5): 616–624. doi:10.1016/j.molcel.2012.03.029. PMID 22560720.
  14. ^ Reitz, Diedre; Chan, Yuen-Ling; Bishop, Douglas K (December 2021). "How strand exchange protein function benefits from ATP hydrolysis". Current Opinion in Genetics & Development. 71: 120–128. doi:10.1016/j.gde.2021.06.016. PMC 8671154. PMID 34343922.
  15. ^ Lesterlin, Christian; Ball, Graeme; Schermelleh, Lothar; Sherratt, David J. (13 February 2014). "RecA bundles mediate homology pairing between distant sisters during DNA break repair". Nature. 506 (7487): 249–253. Bibcode:2014Natur.506..249L. doi:10.1038/nature12868. PMC 3925069. PMID 24362571.
  16. ^ Henkin, Tina M.; Peters, Joseph E.; Snyder, Larry; Champness, Wendy (2020). Snyder & Champness molecular genetics of bacteria (Fifth ed.). Hoboken, NJ: Wiley. p. 259. ISBN 9781555819750.
  17. ^ Akamatsu, Takashi; Taguchi, Hisataka (January 2001). "Incorporation of the Whole Chromosomal DNA in Protoplast Lysates into Competent Cells of Bacillus subtilis". Bioscience, Biotechnology, and Biochemistry. 65 (4): 823–829. doi:10.1271/bbb.65.823. PMID 11388459. S2CID 30118947.
  18. ^ Saito, Yukiko; Taguchi, Hisataka; Akamatsu, Takashi (March 2006). "Fate of transforming bacterial genome following incorporation into competent cells of Bacillus subtilis: a continuous length of incorporated DNA". Journal of Bioscience and Bioengineering. 101 (3): 257–262. doi:10.1263/jbb.101.257. PMID 16716928.
  19. ^ a b Culyba, Matthew J.; Mo, Charlie Y.; Kohli, Rahul M. (16 June 2015). "Targets for Combating the Evolution of Acquired Antibiotic Resistance". Biochemistry. 54 (23): 3573–3582. doi:10.1021/acs.biochem.5b00109. PMC 4471857. PMID 26016604.
  20. ^ Merrikh, Houra; Kohli, Rahul M. (October 2020). "Targeting evolution to inhibit antibiotic resistance". The FEBS Journal. 287 (20): 4341–4353. doi:10.1111/febs.15370. ISSN 1742-464X. PMC 7578009. PMID 32434280.
  21. ^ Wigle, Tim J.; Singleton, Scott F. (June 2007). "Directed molecular screening for RecA ATPase inhibitors". Bioorganic & Medicinal Chemistry Letters. 17 (12): 3249–3253. doi:10.1016/j.bmcl.2007.04.013. PMC 1933586. PMID 17499507.
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