SOS response

The SOS response was articulated by Evelyn Witkin.{{cite journal |last1=Fitzgerald |first1=Devon M. |last2=Hastings |first2=P.J. |last3=Rosenberg |first3=Susan M. |title=Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance |journal=Annual Review of Cancer Biology |date=6 March 2017 |volume=1 |issue=1 |pages=119–140 |doi=10.1146/annurev-cancerbio-050216-121919 |pmid=29399660 |pmc=5794033 |url=https://doi.org/10.1146/annurev-cancerbio-050216-121919 |access-date=6 March 2023 }}{{cite journal |last1=Witkin |first1=E M |title=The radiation sensitivity of Escherichia coli B: a hypothesis relating filament formation and prophage induction. |journal=Proceedings of the National Academy of Sciences |date=May 1967 |volume=57 |issue=5 |pages=1275–9 |doi=10.1073/pnas.57.5.1275 |pmid=5341236 |pmc=224468 |bibcode=1967PNAS...57.1275W |doi-access=free}} Later, by characterizing the phenotypes of mutagenised E. coli, she and post doctoral student Miroslav Radman detailed the SOS response to UV radiation in bacteria.{{Cite journal |last1=Witkin |first1=E. M. |author-link1=Evelyn M. Witkin |title=Ultraviolet mutagenesis and inducible DNA repair in Escherichia coli |journal=Bacteriological Reviews |volume=40 |issue=4 |pages=869–907 |year=1976 |doi =10.1128/MMBR.40.4.869-907.1976 |pmid=795416 |pmc=413988}} The SOS response to DNA damage was a seminal discovery because it was the first coordinated stress response to be elucidated.{{cite journal |title=Phenomenology of an inducible mutagenic DNA repair pathway in Escherichia coli: SOS repair hypothesis |last=Radman |first=M |journal=Basic Life Sciences |year=1975 |volume=5A |pages=355–367 |doi=10.1007/978-1-4684-2895-7_48 |pmid=1103845}}

During normal growth, the SOS genes are under the repressor of the LexA protein. Under normal conditions, LexA binds to a consensus sequence (the SOS box) in the operator region of the SOS regulon genes. Some of these genes are expressed at certain levels even in the repressed state, according to the affinity of LexA for their SOS box. Activation of the SOS genes occurs after DNA damage by the accumulation of single stranded (ssDNA) regions generated at replication forks, where DNA polymerase is blocked. RecA forms a filament around these ssDNA regions in an ATP-dependent fashion, and becomes activated.{{cite journal |title=The SOS system: A complex and tightly regulated response to DNA damage |journal=Environmental and Molecular Mutagenesis |date=May 2019 |volume=60 |issue=4 |pages=368–384 |doi=10.1002/em.22267 |pmc=6590174 |pmid=30447030 |last1=Maslowska |first1=K. H. |last2=Makiela-Dzbenska |first2=K. |last3=Fijalkowska |first3=I. J. |bibcode=2019EnvMM..60..368M}} The activated form of RecA interacts with the LexA repressor to facilitate the LexA repressor's self-cleavage from the operator.{{cite book |last1=Lehninger |first1=Albert L. |last2=Nelson |first2=David Lee |last3=Cox |first3=Michael M. |title=Lehninger principles of biochemistry |date=2005 |publisher=W.H. Freeman |location=New York |isbn=978-0-7167-4339-2 |edition=4th |page=1098 |oclc=55476414}}

Once the pool of LexA decreases, repression of the SOS genes goes down according to the level of LexA affinity for the SOS boxes. Operators that bind LexA weakly are the first to be fully expressed. In this way LexA can sequentially activate different mechanisms of repair. Genes having a weak SOS box (such as lexA, recA, uvrA, uvrB, and uvrD) are fully induced in response to even weak SOS-inducing treatments. Thus the first SOS repair mechanism to be induced is nucleotide excision repair (NER), whose aim is to fix DNA damage without commitment to a full-fledged SOS response. If, however, NER does not suffice to fix the damage, the LexA concentration is further reduced, so the expression of genes with stronger LexA boxes (such as sulA, umuD, umuC – these are expressed late) is induced. SulA stops cell division by binding to FtsZ, the initiating protein in this process. This causes filamentation, and the induction of UmuDC-dependent mutagenic repair. As a result of these properties, some genes may be partially induced in response to even endogenous levels of DNA damage, while other genes appear to be induced only when high or persistent DNA damage is present in the cell.

Research has shown that the SOS response system can lead to mutations which can lead to resistance to antibiotics.{{cite journal | title=Inhibition of mutation and combating the evolution of antibiotic resistance |last1=Cirz | first1=RT |journal=PLOS Biology |date=June 2005 |volume=3 |issue=6 |page=e176 |doi=10.1371/journal.pbio.0030176 |pmid=15869329 |last2=Chin |first2=JK |last3=Andes |first3=DR |last4=De Crécy-Lagard |first4=V |last5=Craig |first5=WA |last6=Romesberg |first6=FE |pmc=1088971 |doi-access=free}} {{open access}} The increased rate of mutation during the SOS response is caused by three low-fidelity DNA polymerases: Pol II, Pol IV and Pol V.{{cite journal |title=Mutations for Worse or Better: Low Fidelity DNA Synthesis by SOS DNA Polymerase V is a Tightly-Regulated Double-Edged Sword |last1=Jaszczur |first1=M |journal=Biochemistry |date=April 2016 |volume=55 |issue=16 |pages=2309–18 | doi=10.1021/acs.biochem.6b00117 | pmid=27043933 |last2=Bertram |first2=JG |last3=Robinson |first3=A |last4=van Oijen |first4=AM |last5=Woodgate |first5=R |last6=Cox |first6=MM |last7=Goodman |first7=MF |pmc=4846499}} Researchers are now targeting these proteins with the aim of creating drugs that prevent SOS repair. By doing so, the time needed for pathogenic bacteria to evolve antibiotic resistance could be extended, thus improving the long term viability of some antibiotic drugs.{{cite journal |title=A molecular target for suppression of the evolution of antibiotic resistance: Inhibition of the Escherichia coli RecA Protein by N6-(1-Naphthyl)-ADP |last1=Lee |first1=AM |last2=Ross |first2=CT |last3=Zeng |first3=BB |last4=Singleton |first4=SF |journal=Journal of Medicinal Chemistry |date=July 2005 |volume=48 |issue=17 |pages=5408–5411 |doi=10.1021/jm050113z |pmid=16107138}}

As well as genetic resistance the SOS response can also promote phenotypic resistance. Here, the genome is preserved whilst other non-genetic factors are altered to enable the bacteria to survive. The SOS dependent tisB-istR toxin-antitoxin system has, for example, been linked to DNA damage-dependent persister cell induction.{{cite journal |title=Ciprofloxacin Causes Persister Formation by Inducing the TisB toxin in Escherichia coli |last1=Dörr |first1=T |journal=PLOS Biology |date=February 2010 |volume=8 |issue=2 |pages=e1000317 |pmc=2826370 |doi=10.1371/journal.pbio.1000317 |pmid=20186264 |last2=Vulić |first2=M |last3=Lewis |first3=K |doi-access=free}}

Image:Genotoxic_Damage.png

In Escherichia coli, different classes of DNA-damaging agents can initiate the SOS response, as described above. Taking advantage of an operon fusion placing the lac operon (responsible for producing beta-galactosidase, a protein which degrades lactose) under the control of an SOS-related protein, a simple colorimetric assay for genotoxicity is possible. A lactose analog is added to the bacteria, which is then degraded by beta-galactosidase, thereby producing a colored compound which can be measured quantitatively through spectrophotometry. The degree of color development is an indirect measure of the beta-galactosidase produced, which itself is directly related to the amount of DNA damage.

The E. coli are further modified in order to have a number of mutations including a uvrA mutation which renders the strain deficient in excision repair, increasing the response to certain DNA-damaging agents, as well as an rfa mutation, which renders the bacteria lipopolysaccharide-deficient, allowing better diffusion of certain chemicals into the cell in order to induce the SOS response.{{cite journal |last1=Quillardet |first1=Philippe |last2=Hofnung |first2=Maurice |title=The SOS chromotest: a review |journal=Mutation Research/Reviews in Genetic Toxicology |date=October 1993 |volume=297 |issue=3 |pages=235–279 |doi=10.1016/0165-1110(93)90019-J |pmid=7692273}} Commercial kits which measures the primary response of the E. coli cell to genetic damage are available and may be highly correlated with the Ames Test for certain materials.{{cite journal |last1=Quillardet |first1=Philippe |last2=de Bellecombe |first2=Christine |last3=Hofnung |first3=Maurice |title=The SOS Chromotest, a colorimetric bacterial assay for genotoxins: validation study with 83 compounds |journal=Mutation Research/Environmental Mutagenesis and Related Subjects |date=June 1985 |volume=147 |issue=3 |pages=79–95 |doi=10.1016/0165-1161(85)90021-4 |pmid=3923333}}

Cyanobacteria, the only prokaryotes capable of oxygen evolving photosynthesis, are major producers of the Earth’s oxygenic atmosphere.{{cite journal |last1=Hamilton |first1=Trinity L. |last2=Bryant |first2=Donald A. |last3=Macalady |first3=Jennifer L. |title=The role of biology in planetary evolution: cyanobacterial primary production in low-oxygen Proterozoic oceans |journal=Environmental Microbiology |date=February 2016 |volume=18 |issue=2 |pages=325–340 |doi=10.1111/1462-2920.13118 |pmid=26549614 |pmc=5019231}} The marine cyanobacteria Prochlorococcus and Synechococcus appear to have an E. coli like SOS system for repair of DNA, since they encode genes homologous to key E. coli SOS genes such as lexA and sulA.{{cite journal |last1=Cassier-Chauvat |first1=Corinne |last2=Veaudor |first2=Théo |last3=Chauvat |first3=Franck |title=Comparative Genomics of DNA Recombination and Repair in Cyanobacteria: Biotechnological Implications |journal=Frontiers in Microbiology |date=9 November 2016 |volume=7 |page=1809 |doi=10.3389/fmicb.2016.01809 |pmid=27881980 |pmc=5101192 |doi-access=free}}

File:Filamentation 1.jpg|The SOS response inhibits septum formation until bacterial DNA can be repaired and is observable as filamentation when cells are examined by microscopy (top right of image).

• Induction of lysis in lambda phage

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Category:DNA repair