Abstract
The bacterial SOS response is an elaborate program for DNA repair, cell cycle regulation and adaptive mutagenesis under stress conditions. Using sensitive sequence and structure analysis, combined with contextual information derived from comparative genomics and domain architectures, we identify two novel domain superfamilies in the SOS response system. We present evidence that one of these, the SOS response associated peptidase (SRAP; Pfam: DUF159) is a novel thiol autopeptidase. Given the involvement of other autopeptidases, such as LexA and UmuD, in the SOS response, this finding suggests that multiple structurally unrelated peptidases have been recruited to this process. The second of these, the ImuB-C superfamily, is linked to the Y-family DNA polymerase-related domain in ImuB, and also occurs as a standalone protein. We present evidence using gene neighborhood analysis that both these domains function with different mutagenic polymerases in bacteria, such as Pol IV (DinB), Pol V (UmuCD) and ImuA-ImuB-DnaE2 and also other repair systems, which either deploy Ku and an ATP-dependent ligase or a SplB-like radical SAM photolyase. We suggest that the SRAP superfamily domain functions as a DNA-associated autoproteolytic switch that recruits diverse repair enzymes upon DNA damage, whereas the ImuB-C domain performs a similar function albeit in a non-catalytic fashion. We propose that C3Orf37, the eukaryotic member of the SRAP superfamily, which has been recently shown to specifically bind DNA with 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine, is a sensor for these oxidized bases generated by the TET enzymes from methylcytosine. Hence, its autoproteolytic activity might help it act as a switch that recruits DNA repair enzymes to remove these oxidized methylcytosine species as part of the DNA demethylation pathway downstream of the TET enzymes.ReviewersThis article was reviewed by RDS, RF and GJ.
Highlights
The bacterial SOS, first described by Radman about 40 years ago, is a versatile stress-induced network for DNA repair, mutagenesis, cell cycle regulation and adaptation [1,2,3,4]
Given the everincreasing accumulation of genomic data we performed a new systematic collection of the gene-neighborhoods centered on these operon types by searching 11,123 bacterial genomes deposited in the Genbank database
As a result we identified two uncharacterized superfamilies that tended to strongly co-occur with the mutagenic SOS operons across most major lineages of the bacterial tree (Figure 1 and Additional file 1; 25 and 65% of all their recovered gene neighborhood showed such associations)
Summary
The bacterial SOS, first described by Radman about 40 years ago, is a versatile stress-induced network for DNA repair, mutagenesis, cell cycle regulation and adaptation [1,2,3,4]. At its heart lies a DNA-damage sensor comprised of the LexA repressor, which combines a signal peptidase-like serine peptidase domain with a DNA-binding winged helixturn-helix (wHTH) domain, and RecA, which is a P-loop ATPase that catalyzes strand exchange during homologous recombination [2,3]. The access of RecA to single stranded DNA is barred by the single-strand-binding protein. When DNA is damaged by single strand lesions, the RecFOR complex, and when by double-strand breaks, the RecBC complex, help RecA to gain access to DNA [5]. When RecA polymerizes as a filament on ssDNA it facilitates the peptidase domain of LexA to catalyze autoproteolysis. Autoproteolysis of LexA in turn allows transcription of genes repressed by it, thereby initiating the SOS response [1,2,4,6]
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