LexA repressor
| LexA DNA binding domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 lexa s119a mutant | |||||||||
| Identifiers | |||||||||
| Symbol | LexA_DNA_bind | ||||||||
| Pfam | PF01726 | ||||||||
| Pfam clan | CL0123 | ||||||||
| InterPro | IPR006199 | ||||||||
| SCOP2 | 1leb / SCOPe / SUPFAM | ||||||||
| |||||||||
The LexA repressor or LexA (Locus for X-ray sensitivity A)[1] is a transcriptional repressor (EC 3.4.21.88) that represses SOS response genes coding primarily for error-prone DNA polymerases, DNA repair enzymes and cell division inhibitors.[2] LexA forms de facto a two-component regulatory system with RecA, which senses DNA damage at stalled replication forks, forming monofilaments and acquiring an active conformation capable of binding to LexA and causing LexA to cleave itself, in a process called autoproteolysis.[1]
LexA polypeptides contains a two domains: a DNA-binding domain and a dimerization domain.[3] The dimerization domain binds to other LexA polypeptides to form dumbbell shaped dimers. The DNA-binding domain is a variant form of the helix-turn-helix DNA binding motif,[4] and is usually located at the N-terminus of the protein.[1] This domain is bound to an SOS box upstream of SOS response genes until DNA damage stimulates autoproteolysis.[3]
Clinical significance
[edit]DNA damage can be inflicted by the action of antibiotics, bacteriophages, and UV light.[2] Of potential clinical interest is the induction of the SOS response by antibiotics, such as ciprofloxacin. Bacteria require topoisomerases such as DNA gyrase or topoisomerase IV for DNA replication. Antibiotics such as ciprofloxacin are able to prevent the action of these molecules by attaching themselves to the gyrate–DNA complex, leading to replication fork stall and the induction of the SOS response. The expression of error-prone polymerases under the SOS response increases the basal mutation rate of bacteria. While mutations are often lethal to the cell, they can also enhance survival. In the specific case of topoisomerases, some bacteria have mutated one of their amino acids so that the ciprofloxacin can only create a weak bond to the topoisomerase. This is one of the methods that bacteria use to become resistant to antibiotics. Ciprofloxacin treatment can therefore potentially lead to the generation of mutations that may render bacteria resistant to ciprofloxacin. In addition, ciprofloxacin has also been shown to induce via the SOS response dissemination of virulence factors[5] and antibiotic resistance determinants,[6] as well as the activation of integron integrases,[7] potentially increasing the likelihood of acquisition and dissemination of antibiotic resistance by bacteria.[2]
Impaired LexA proteolysis has been shown to interfere with ciprofloxacin resistance.[8] This offers potential for combination therapy that combines quinolones with strategies aimed at interfering with the action of LexA, either directly or via RecA.
References
[edit]- ^ a b c Butala M, Žgur-Bertok D, Busby SJ (January 2009). "The bacterial LexA transcriptional repressor". Cellular and Molecular Life Sciences. 66 (1): 82–93. doi:10.1007/s00018-008-8378-6. PMC 11131485. PMID 18726173. S2CID 29537019.
- ^ a b c Erill I, Campoy S, Barbé J (November 2007). "Aeons of distress: an evolutionary perspective on the bacterial SOS response". FEMS Microbiology Reviews. 31 (6): 637–656. doi:10.1111/j.1574-6976.2007.00082.x. PMID 17883408.
- ^ a b Henkin TM, Peters JE (2020). "DNA Repair and Mutagenesis". Snyder and Champness molecular genetics of bacteria (Fifth ed.). Hoboken, NJ : Washington, D.C: John Wiley & Sons, Inc. ISBN 9781555819750.
- ^ Fogh RH, Ottleben G, Rüterjans H, Schnarr M, Boelens R, Kaptein R (September 1994). "Solution structure of the LexA repressor DNA binding domain determined by 1H NMR spectroscopy". The EMBO Journal. 13 (17): 3936–3944. doi:10.1002/j.1460-2075.1994.tb06709.x. PMC 395313. PMID 8076591.
- ^ Ubeda C, Maiques E, Knecht E, Lasa I, Novick RP, Penadés JR (May 2005). "Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in staphylococci". Molecular Microbiology. 56 (3): 836–844. doi:10.1111/j.1365-2958.2005.04584.x. PMID 15819636.
- ^ Beaber JW, Hochhut B, Waldor MK (January 2004). "SOS response promotes horizontal dissemination of antibiotic resistance genes". Nature. 427 (6969): 72–74. Bibcode:2004Natur.427...72B. doi:10.1038/nature02241. PMID 14688795. S2CID 4300746.
- ^ Guerin E, Cambray G, Sanchez-Alberola N, Campoy S, Erill I, Da Re S, et al. (May 2009). "The SOS response controls integron recombination". Science. 324 (5930): 1034. Bibcode:2009Sci...324.1034G. doi:10.1126/science.1172914. PMID 19460999. S2CID 42334786.
- ^ Cirz RT, Chin JK, Andes DR, de Crécy-Lagard V, Craig WA, Romesberg FE (June 2005). "Inhibition of mutation and combating the evolution of antibiotic resistance". PLOS Biology. 3 (6): e176. doi:10.1371/journal.pbio.0030176. PMC 1088971. PMID 15869329.
| Excision repair | |
|---|---|
| Homologous recombination | |
| Other pathways | |
| Regulation | |
| Other/ungrouped | |
