User talk:KPSR09

Introduction
The bacterial SOS repair mechanism is a versatile stress-induced network for DNA repair, mutagenesis, cell cycle regulation and adaptation. The mechanisms developed to tolerate the DNA damage include photoreactivation, excision repair, post replicative trans-lesion bypass repair and SOS response. SOS, a mutagenic repair mechanism is triggered when the other mechanisms fail due to increased amount of damage.

Discovery
SOS repair and SOS mutagenesis were discovered by Jean Weigle in 1953, who observed that pre-irradiation of the bacterial host increased survival of UV-irradiated phage λ. The SOS hypothesis stated “the existence of a DNA repair system which is normally repressed but which is induced by DNA damage”. When applied to phage DNA, SOS phenomena is called Weigle reactivation. The hypothesis was amplified and developed by Miroslav Radman in 1975.

Mechanism
SOS DNA repair system mainly comprises of recA,umu D and C genes which constitute an operon repressed by lexA (autoregulated). The SOS genes are repressed by the protein LexA which binds at SOS box present in the promoter region of each gene. When the cells are exposed to UV radiation the DNA is damaged and replication fork is stalled, which stimulates the RecA to polymerize on ssDNA gaps (intracellular signal) forming RecA* coprotease facilitating the autoproteolysis of LexA. Autoproteolysis of LexA allows the enhanced gene expression of the SOS genes causing the initiation of SOS response.

All the SOS genes are not induced at the same time and to the same level. The first genes to be induced are uvrA, uvrB, and uvrD. These proteins together with UvrC endonuclease form UvrABD complex, which mediates the excision of nucleotides (Nucleotide excision repair) from damaged DNA. As a second level of defense against DNA lesions, expression of recA increases, and repair by homologous recombination is initiated. This is followed by inhibition of cell division by sulA and sulB genes causing filamentation and prolonging the time of cellular DNA repair. The final module of SOS repair involves the induction of DNA polymerase V (comprised of UmuC and UmuD) which synthesizes DNA over lesions. This allows the cell to survive the lesions at the cost of mutagenesis, caused due to error prone nature of Pol V.

Regulation
The SOS response is an induced DNA repair system which is characterised by early accurate DNA repair phase followed by a more mutagenic damage tolerant phase. The up and down regulation of the SOS-induced genes is an interplay of two proteins, LexA and RecA*. The final phase of DNA damage induced mutagenesis is regulated by intracellular products of umuC and umuD genes.

Transcriptional regulation
The transcription of the SOS genes is regulated by the LexA protein which inhibits the expression of these genes. The ssDNA gaps produced due to DNA damage acts as signal for activation of RecA protein forming RecA* filament. RecA* catalyses the cleavage of LexA protein from the promoter region of SOS genes thus, activating the SOS genes.The LexA protein is constantly produced in the cell which ensures the protein re-accumulation thus repressing the SOS genes as soon as the signal ,(i.e. ssDNA) disappears.

RecA* Complex regulation
The UV radiation leads to DNA damage causing single strand lesions. The protein RecFOR assists RecA in binding to these single stranded gaps. RecFOR complex is a heterotrimeric complex composed of the subunits RecF, RecO and RecR which mediate the loading of RecA protein specifically onto single-strand DNA binding proteins coated gapped DNA during DNA repair. RecFOR recognizes the junction between ssDNA and dsDNA regions and acts as a structural specific mediator that targets recombinational DNA repair. SOS, induced by UV light is initiated by RecFOR proteins whereas for DNA double-strand breaks, caused by agents like topoisomerase poisons, RecBC complex helps RecA to gain access to DNA.

Regulation by Proteolysis
Regulation of the intracellular levels of umuD, umuD’,and umuC is achieved by the Lon and ClpXP Serine Proteases. Lon degrades UmuD and UmuC proteins before they become mutagenically active. ClpXP degrades UmuD’, the mutagenically active form of UmuD. RecA* coprotease initiates UmuD → UmuD’. The monomeric UmuD' protein can undertake two paths, where it

(i) forms homodimers (UmuD’-UmuD’), which then interacts with UmuC to form stable mutagenically active UmuD’2C Complex(Pol V)

(ii) heterodimerizes with UmuD.

If the second pathway is chosen, UmuD’ is rapidly degraded by ClpXP releasing UmuD protein which can be degraded Lon. Binding of UmuC to UmuD’, masks the activity of Lon on UmuC. Limited UmuD cleavage occurs under non SOS conditions.

Eukaryotic Homologue
Recent studies determined that DNA damage in human skin cells by ultraviolet radiation stimulates photoprotective response, a DNA repair mechanism functionally similar to the SOS response described in bacteria. It is seen that Thymidine dinucleotide( pTpT) act as powerful probes of DNA damage responses, which initiates the response by activating p53, a tumour suppresor gene. Similar to bacterial SOS response, pTpT upregulates DNA repair enzymes and enhances the DNA repair capacity of human skin cells by increasing transient growth arrest whereas p53 binds to single-stranded DNA facilitating strand renaturation, reflecting a direct role in DNA repair.