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RecA

From Wikipedia, in a visual modern way
recA bacterial DNA recombination protein
Homologous recombination 3cmt.png
Crystal structure of a RecA-DNA complex. PDB ID: 3cmt.[1]
Identifiers
SymbolRecA
PfamPF00154
Pfam clanCL0023
InterProIPR013765
PROSITEPDOC00131
SCOP22reb / SCOPe / SUPFAM

RecA is a 38 kilodalton protein essential for the repair and maintenance of DNA.[2] A RecA structural and functional homolog has been found in every species in which one has been seriously sought and serves as an archetype for this class of homologous DNA repair proteins. The homologous protein is called RAD51 in eukaryotes and RadA in archaea.[3][4]

RecA has multiple activities, all related to DNA repair. In the bacterial SOS response, it has a co-protease[5] function in the autocatalytic cleavage of the LexA repressor and the λ repressor.[6]

RecA's association with DNA repair is based on its central role in homologous recombination. The RecA protein binds strongly and in long clusters to ssDNA to form a nucleoprotein filament. 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.[7] In some bacteria, RecA posttranslational modification via phosphorylation of a serine residue on Loop 2 can interfere with homologous recombination.[8]

The search process induces stretching of the DNA duplex, which enhances sequence complementarity recognition (a mechanism termed conformational proofreading[9][10]). 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.

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.[11]

E. coli strains deficient in RecA are useful for cloning procedures in molecular biology laboratories. E. coli strains are often genetically modified to contain a mutant recA allele and thereby ensure the stability of extrachromosomal segments of DNA, known as plasmids. In a process called transformation, plasmid DNA is taken up by the bacteria under a variety of conditions. Bacteria containing exogenous plasmids are called "transformants". Transformants retain the plasmid throughout cell divisions such that it can be recovered and used in other applications. Without functional RecA protein, the exogenous plasmid DNA is left unaltered by the bacteria. Purification of this plasmid from bacterial cultures can then allow high-fidelity PCR amplification of the original plasmid sequence.

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Dalton (unit)

Dalton (unit)

The dalton or unified atomic mass unit is a non-SI unit of mass widely used in physics and chemistry. It is defined as 1⁄12 of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. The atomic mass constant, denoted mu, is defined identically, giving mu = m(12C)/12 = 1 Da.

DNA

DNA

Deoxyribonucleic acid is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids. Alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.

Archaea

Archaea

Archaea is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria, but this term has fallen out of use.

DNA repair

DNA repair

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

Binding site

Binding site

In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may include other proteins, enzyme substrates, second messengers, hormones, or allosteric modulators. The binding event is often, but not always, accompanied by a conformational change that alters the protein's function. Binding to protein binding sites is most often reversible, but can also be covalent reversible or irreversible.

Conformational proofreading

Conformational proofreading

Conformational proofreading or conformational selection is a general mechanism, suggested by Yonatan Savir and Tsvi Tlusty, of molecular recognition systems in which introducing a structural mismatch between a molecular recognizer and its target, or an energetic barrier, enhances the recognition specificity and quality. Conformational proofreading does not require the consumption of energy and may therefore be used in any molecular recognition system. Conformational proofreading is especially useful in scenarios where the recognizer has to select the appropriate target among many similar competitors.

ATPase

ATPase

ATPases (EC 3.6.1.3, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or the inverse reaction. This dephosphorylation reaction releases energy, which the enzyme (in most cases) harnesses to drive other chemical reactions that would not otherwise occur. This process is widely used in all known forms of life.

Binding constant

Binding constant

The binding constant, or association constant, is a special case of the equilibrium constant K, and is the inverse of the dissociation constant. It is associated with the binding and unbinding reaction of receptor (R) and ligand (L) molecules, which is formalized as:R + L ⇌ RL

Adenosine diphosphate

Adenosine diphosphate

Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbone attached to adenine and two phosphate groups bonded to the 5 carbon atom of ribose. The diphosphate group of ADP is attached to the 5’ carbon of the sugar backbone, while the adenine attaches to the 1’ carbon.

Escherichia coli

Escherichia coli

Escherichia coli, also known as E. coli, is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus Escherichia that is commonly found in the lower intestine of warm-blooded organisms. Most E. coli strains are harmless, but some serotypes (EPEC, ETEC etc.) can cause serious food poisoning in their hosts, and are occasionally responsible for food contamination incidents that prompt product recalls. Most strains do not cause disease in humans and are part of the normal microbiota of the gut; such strains are harmless or even beneficial to humans (although these strains tend to be less studied than the pathogenic ones). For example, some strains of E. coli benefit their hosts by producing vitamin K2 or by preventing the colonization of the intestine by pathogenic bacteria. These mutually beneficial relationships between E. coli and humans are a type of mutualistic biological relationship — where both the humans and the E. coli are benefitting each other. E. coli is expelled into the environment within fecal matter. The bacterium grows massively in fresh faecal matter under aerobic conditions for three days, but its numbers decline slowly afterwards.

DNA replication

DNA replication

In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part of biological inheritance. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA. The cell possesses the distinctive property of division, which makes replication of DNA essential.

Allele

Allele

An allele is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.The word "Allele" is a short form of "allelomorph". "The chromosomal or genomic location of a gene or any other genetic element is called a locus and alternative DNA sequences at a locus are called alleles."

Potential as a drug target

Wigle and Singleton at the University of North Carolina have shown that small molecules interfering with RecA function in the cell may be useful in the creation of new antibiotic drugs.[12] 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. Additionally the activities of RecA are synonymous with antibiotic resistance development, and inhibitors of RecA may also serve to delay or prevent the appearance of bacterial drug resistance.

Role of RecA in natural transformation

Based on analysis of the molecular properties of the RecA system, Cox[13] concluded that the data "provide compelling evidence that the primary mission of RecA protein is DNA repair." In a further essay on the function of the RecA protein, Cox[14] summarized data demonstrating that "RecA protein evolved as the central component of a recombinational DNA repair system, with the generation of genetic diversity as a sometimes useful byproduct."

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 (see Transformation (genetics)). Transformation, in which RecA plays a central role, depends on expression of numerous additional gene products (e.g. about 40 gene products in Bacillus subtilis) that specifically interact to carry out this process indicating that it is an evolved adaptation for DNA transfer. In B. subtilis the length of the transferred DNA can be as great as a third and up to the size of the whole chromosome.[15][16] In order for a bacterium to bind, take up and recombine exogenous DNA into its chromosome, it must first enter a special physiological state termed "competence" (see Natural competence). Transformation is common in the prokaryotic world, and thus far 67 species are known to be competent for transformation.[17]

One of the most well studied transformation systems is that of B. subtilis. In this bacterium, the RecA protein interacts with the incoming single-stranded DNA (ssDNA) to form striking filamentous structures.[18] These RecA/ssDNA filaments emanate from the cell pole containing the competence machinery and extend into the cytosol. The RecA/ssDNA filamentous threads are considered to be dynamic nucleofilaments that scan the resident chromosome for regions of homology. This process brings the incoming DNA to the corresponding site in the B. subtilis chromosome where informational exchange occurs.

Michod et al.[19] have reviewed evidence that RecA-mediated transformation is an adaptation for homologous recombinational repair of DNA damage in B. subtilis, as well as in several other bacterial species (i.e. Neisseria gonorrhoeae, Hemophilus influenzae, Streptococcus pneumoniae, Streptococcus mutans and Helicobacter pylori). In the case of the pathogenic species that infect humans, it was proposed that RecA-mediated repair of DNA damages may be of substantial benefit when these bacteria are challenged by the oxidative defenses of their host.

Discover more about Role of RecA in natural transformation related topics

DNA repair

DNA repair

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

DNA

DNA

Deoxyribonucleic acid is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids. Alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.

Species

Species

In biology, a species is often defined as the largest group of organisms in which any two individuals of the appropriate sexes or mating types can produce fertile offspring, typically by sexual reproduction. It is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. Other ways of defining species include their karyotype, DNA sequence, morphology, behaviour, or ecological niche. In addition, paleontologists use the concept of the chronospecies since fossil reproduction cannot be examined.

Homologous recombination

Homologous recombination

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

Bacillus subtilis

Bacillus subtilis

Bacillus subtilis, known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus Bacillus, B. subtilis is rod-shaped, and can form a tough, protective endospore, allowing it to tolerate extreme environmental conditions. B. subtilis has historically been classified as an obligate aerobe, though evidence exists that it is a facultative anaerobe. B. subtilis is considered the best studied Gram-positive bacterium and a model organism to study bacterial chromosome replication and cell differentiation. It is one of the bacterial champions in secreted enzyme production and used on an industrial scale by biotechnology companies.

Adaptation

Adaptation

In biology, adaptation has three related meanings. Firstly, it is the dynamic evolutionary process of natural selection that fits organisms to their environment, enhancing their evolutionary fitness. Secondly, it is a state reached by the population during that process. Thirdly, it is a phenotypic trait or adaptive trait, with a functional role in each individual organism, that is maintained and has evolved through natural selection.

Chromosome

Chromosome

A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are the histones. These proteins, aided by chaperone proteins, bind to and condense the DNA molecule to maintain its integrity. These chromosomes display a complex three-dimensional structure, which plays a significant role in transcriptional regulation.

Natural competence

Natural competence

In microbiology, genetics, cell biology, and molecular biology, competence is the ability of a cell to alter its genetics by taking up extracellular ("naked") DNA from its environment in the process called transformation. Competence may be differentiated between natural competence, a genetically specified ability of bacteria which is thought to occur under natural conditions as well as in the laboratory, and induced or artificial competence, which arises when cells in laboratory cultures are treated to make them transiently permeable to DNA. Competence allows for rapid adaptation and DNA repair of the cell. This article primarily deals with natural competence in bacteria, although information about artificial competence is also provided.

Neisseria gonorrhoeae

Neisseria gonorrhoeae

Neisseria gonorrhoeae, also known as gonococcus (singular), or gonococci (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gonorrhea as well as other forms of gonococcal disease including disseminated gonococcemia, septic arthritis, and gonococcal ophthalmia neonatorum.

Streptococcus pneumoniae

Streptococcus pneumoniae

Streptococcus pneumoniae, or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic member of the genus Streptococcus. They are usually found in pairs (diplococci) and do not form spores and are non motile. As a significant human pathogenic bacterium S. pneumoniae was recognized as a major cause of pneumonia in the late 19th century, and is the subject of many humoral immunity studies.

Streptococcus mutans

Streptococcus mutans

Streptococcus mutans is a facultatively anaerobic, gram-positive coccus commonly found in the human oral cavity and is a significant contributor to tooth decay. It is part of the "streptococci", an informal general name for all species in the genus Streptococcus. The microbe was first described by James Kilian Clarke in 1924.

Helicobacter pylori

Helicobacter pylori

Helicobacter pylori, previously known as Campylobacter pylori, is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape is thought to have evolved in order to penetrate the mucoid lining of the stomach and thereby establish infection. The bacterium was first identified in 1982 by the Australian doctors Barry Marshall and Robin Warren. H. pylori has been associated with cancer of the mucosa-associated lymphoid tissue in the stomach, esophagus, colon, rectum, or tissues around the eye, and of lymphoid tissue in the stomach.

Source: "RecA", Wikipedia, Wikimedia Foundation, (2022, November 24th), https://en.wikipedia.org/wiki/RecA.

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Further Reading

Genetic recombination

Prophage

Transformation (genetics)

RecBCD

Bacillus subtilis

Non-homologous end joining

Mycobacterium smegmatis

Homologous recombination

Natural competence

Circular chromosome
References
  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. (1980). "Organization of the recA gene of Escherichia coli". Proc. Natl. Acad. Sci. U.S.A. 77 (1): 313–317. Bibcode:1980PNAS...77..313H. doi:10.1073/pnas.77.1.313. PMC 348260. PMID 6244554.
  3. ^ 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.
  4. ^ 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.
  5. ^ Horii T.; Ogawa T.; Nakatani T.; Hase T.; Matsubara H. & Ogawa H. (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.
  6. ^ Little JW (1984). "Autodigestion of lexA and phage lambda repressors". Proc Natl Acad Sci USA. 81 (5): 1375–1379. Bibcode:1984PNAS...81.1375L. doi:10.1073/pnas.81.5.1375. PMC 344836. PMID 6231641.
  7. ^ Maraboeuf F, Voloshin O, Camerini-Otero RD, Takahashi M (1995). "The central aromatic residue in loop L2 of RecA interacts with DNA. Quenching of the fluorescence of a tryptophan reporter inserted in L2 upon binding to DNA". J Biol Chem. 270 (52): 30927–32. doi:10.1074/jbc.270.52.30927. PMID 8537348.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Wipperman MF, Heaton BE, Nautiyal A, Adefisayo O, Evans H, Gupta R; et al. (2018). "Mycobacterial Mutagenesis and Drug Resistance Are Controlled by Phosphorylation- and Cardiolipin-Mediated Inhibition of the RecA Coprotease". Mol Cell. 72 (1): 152–161.e7. doi:10.1016/j.molcel.2018.07.037. PMC 6389330. PMID 30174294.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Savir Y, Tlusty T (2010). "RecA-mediated homology search as a nearly optimal signal detection system". Molecular Cell. 40 (3): 388–96. arXiv:1011.4382. doi:10.1016/j.molcel.2010.10.020. PMID 21070965. S2CID 1682936.
  10. ^ De Vlaminck I, van Loenhout MT, Zweifel L, den Blanken J, Hooning K, Hage S, Kerssemakers J, Dekker C (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.
  11. ^ Lesterlin C, Ball G, Schermelleh L, Sherratt DJ (2014). "RecA bundles mediate homology pairing between distant sisters during DNA break repair". Nature. 506 (7487): 249–53. Bibcode:2014Natur.506..249L. doi:10.1038/nature12868. PMC 3925069. PMID 24362571.
  12. ^ Wigle TJ, Singleton SF (June 2007). "Directed molecular screening for RecA ATPase inhibitors". Bioorg. Med. Chem. Lett. 17 (12): 3249–53. doi:10.1016/j.bmcl.2007.04.013. PMC 1933586. PMID 17499507.
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  14. ^ Cox MM (September 1993). "Relating biochemistry to biology: how the recombinational repair function of RecA protein is manifested in its molecular properties". BioEssays. 15 (9): 617–23. doi:10.1002/bies.950150908. PMID 8240315.
  15. ^ Akamatsu T, Taguchi H (April 2001). "Incorporation of the whole chromosomal DNA in protoplast lysates into competent cells of Bacillus subtilis". Biosci. Biotechnol. Biochem. 65 (4): 823–9. doi:10.1271/bbb.65.823. PMID 11388459. S2CID 30118947.
  16. ^ Saito Y, Taguchi H, Akamatsu T (March 2006). "Fate of transforming bacterial genome following incorporation into competent cells of Bacillus subtilis: a continuous length of incorporated DNA". J. Biosci. Bioeng. 101 (3): 257–62. doi:10.1263/jbb.101.257. PMID 16716928.
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  19. ^ Michod RE, Bernstein H, Nedelcu AM (May 2008). "Adaptive value of sex in microbial pathogens". Infect. Genet. Evol. 8 (3): 267–85. doi:10.1016/j.meegid.2008.01.002. PMID 18295550.
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