SOS Response
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The SOS response is a global response to DNA damage in which the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
is arrested and
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 dam ...
and
mutagenesis Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using lab ...
is induced. The system involves the
RecA RecA is a 38 kilodalton protein essential for the repair and maintenance of DNA. 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 homolog ...
protein ( Rad51 in eukaryotes). The RecA protein, stimulated by single-stranded DNA, is involved in the inactivation of the repressor (
LexA Repressor LexA or LexA is a transcriptional repressor () that represses SOS response genes coding primarily for error-prone DNA polymerases, DNA repair enzymes and cell division inhibitors. LexA forms ''de facto'' a two-component regulatory system ...
) of SOS response genes thereby inducing the response. It is an error-prone repair system that contributes significantly to DNA changes observed in a wide range of species.


Discovery

The SOS response was discovered and named by Miroslav Radman in 1975.


Mechanism

During normal growth, the SOS genes are negatively regulated by
LexA Repressor LexA or LexA is a transcriptional repressor () that represses SOS response genes coding primarily for error-prone DNA polymerases, DNA repair enzymes and cell division inhibitors. LexA forms ''de facto'' a two-component regulatory system ...
repressor protein In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
dimers. Under normal conditions,
LexA Repressor LexA or LexA is a transcriptional repressor () that represses SOS response genes coding primarily for error-prone DNA polymerases, DNA repair enzymes and cell division inhibitors. LexA forms ''de facto'' a two-component regulatory system ...
binds to a 20-bp consensus sequence (the
SOS box SOS box is the region in the promoter of various genes to which the LexA repressor binds to repress the transcription of SOS-induced proteins. This occurs in the absence of DNA damage. In the presence of DNA damage the binding of LexA is inactiva ...
) in the operator region for those genes. Some of these SOS 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 A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
is blocked. RecA forms a filament around these ssDNA regions in an ATP-dependent fashion, and becomes activated. The activated form of RecA interacts with the LexA repressor to facilitate the LexA repressor's self-cleavage from the operator. Once the pool of
LexA Repressor LexA or LexA is a transcriptional repressor () that represses SOS response genes coding primarily for error-prone DNA polymerases, DNA repair enzymes and cell division inhibitors. LexA forms ''de facto'' a two-component regulatory system ...
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 SOSbox (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 Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
by binding to
FtsZ FtsZ is a protein encoded by the ''ftsZ'' gene that assembles into a ring at the future site of bacterial cell division (also called the Z ring). FtsZ is a prokaryotic homologue of the eukaryotic protein tubulin. The initials FtsZ mean "Filamen ...
, the initiating protein in this process. This causes
filamentation Filamentation is the anomalous growth of certain bacteria, such as ''Escherichia coli'', in which cells continue to elongate but do not divide (no septa formation). The cells that result from elongation without division have multiple chromosomal c ...
, 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.


Antibiotic resistance

Research has shown that the SOS response system can lead to mutations which can lead to resistance to antibiotics. The increased rate of mutation during the SOS response is caused by three low-fidelity
DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
s: Pol II, Pol IV and
Pol V DNA Polymerase V (Pol V) is a polymerase enzyme involved in DNA repair mechanisms in bacteria, such as ''Escherichia coli''. It is composed of a UmuD' homodimer and a UmuC monomer, forming the UmuD'2C protein complex. It is part of the Y-family o ...
. 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. 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 A toxin-antitoxin system is a set of two or more closely linked genes that together encode both a "toxin" protein and a corresponding "antitoxin". Toxin-antitoxin systems are widely distributed in prokaryotes, and organisms often have them in mult ...
has, for example, been linked to DNA damage-dependent persister cell induction.


Genotoxicity testing

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 The ''lactose'' operon (''lac'' operon) is an operon required for the transport and metabolism of lactose in ''E. coli'' and many other enteric bacteria. Although glucose is the preferred carbon source for most bacteria, the ''lac'' operon allows ...
(responsible for producing beta-galactosidase, a protein which degrades lactose) under the control of an SOS-related protein, a simple colorimetric assay for
genotoxicity Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic su ...
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 Spectrophotometry is a branch of electromagnetic spectroscopy concerned with the quantitative measurement of the reflection or transmission properties of a material as a function of wavelength. Spectrophotometry uses photometers, known as spec ...
. 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. 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.


Additional images

File:Filamentation 1.jpg, The SOS response inhibits septum formation until bacterial DNA can be repaired and is observable as
filamentation Filamentation is the anomalous growth of certain bacteria, such as ''Escherichia coli'', in which cells continue to elongate but do not divide (no septa formation). The cells that result from elongation without division have multiple chromosomal c ...
when cells are examined by microscopy (top right of image).


See also

* Induction of lysis in lambda phage


References

{{DEFAULTSORT:Sos Response 1975 in science DNA repair