The SOS response is a global response to DNA damage in which the cell cycle 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 da ...

and mutagenesis is induced. The system involves the RecA protein ( Rad51 in eukaryotes). The RecA protein, stimulated by single-stranded DNA, is involved in the inactivation of the repressor ( LexA) 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 protein dimers. Under normal conditions, LexA binds to a 20-bp consensus sequence (the SOS box) 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 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 Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucle ...

(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 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 Resistance may refer to: Arts, entertainment, and media Comics * Either of two similarly named but otherwise unrelated comic book series, both published by Wildstorm: ** ''Resistance'' (comics), based on the video game of the same title ** ''T ...

to antibiotics. The increased rate of mutation during the SOS response is caused by three low-fidelity

Pol II DNA polymerase II (also known as DNA Pol II or Pol II) is a prokaryotic DNA-Dependent DNA polymerase encoded by the PolB gene. DNA Polymerase II is an 89.9-kDa protein and is a member of the B family of DNA polymerases. It was originally isolated ...

Pol IV DNA polymerase IV is a prokaryotic polymerase that is involved in mutagenesis and is encoded by the ''dinB'' gene. It exhibits no 3′→5′ exonuclease (proofreading) activity and hence is error prone. In ''E. coli'', DNA polymerase IV (Pol 4) i ...

and Pol V. 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 has, for example, been linked to DNA damage-dependent

persister cell Persister cells are subpopulations of cells that resist treatment, and become antimicrobial tolerant by changing to a state of dormancy or quiescence. Persister cells in their dormancy do not divide. The tolerance shown in persister cells differs f ...

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 (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 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 sp ...

. 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

when cells are examined by microscopy (top right of image).

References