DNA damage responses in prokaryotes: regulating gene expression, modulating growth patterns, and manipulating replication forks

Abstract

Recent advances in the area of bacterial DNA damage responses are reviewed here. The SOS pathway is still the major paradigm of bacterial DNA damage response, and recent studies have clarified the mechanisms of SOS induction and key physiological roles of SOS including a very major role in genetic exchange and variation. When considering diverse bacteria, it is clear that SOS is not a uniform pathway with one purpose, but rather a platform that has evolved for differing functions in different bacteria. Relating in part to the SOS response, the field has uncovered multiple apparent cell-cycle checkpoints that assist cell survival after DNA damage and remarkable pathways that induce programmed cell death in bacteria. Bacterial DNA damage responses are also much broader than SOS, and several important examples of LexA-independent regulation will be reviewed. Finally, some recent advances that relate to the replication and repair of damaged DNA will be summarized.

Figure 1.

The E. coli SOS response. The basic circuitry of the E. coli SOS response is summarized. RecA protein-DNA filaments serve as a coprotease to activate self-cleavage of the LexA protein, the global repressor of SOS. As described in the text, RecA can also activate self-cleavage of UmuD and the phage λ repressor.

Figure 2.

Factors implicated in DNA damage-inducible modulation of bacterial cell growth and death. Proteins and other factors that have been implicated in checkpoint induction, persister cell formation, and programmed cell death are depicted. Subsets of these proteins may act in distinct pathways; the diagram does not imply that all proteins next to an arrow act together. See text for details.

Figure 3.

SOS-independent DNA damage responses. (A) In the adaptive response, transfer of an alkyl group from DNA to the Cys-38 residue of the Ada protein generates the activator for the adaptive response, which promotes transcription of the ada gene along with alkA, alkB, and aidB genes. (B) Most damage-inducible genes in mycobacteria are regulated by ClpR, a transcriptional activator that binds to the promoter region of its own gene as well as that of the recA, clpP, and other regulon genes. The recA gene is also controlled by LexA and the SOS response from the second of two recA promoters.

Figure 4.

Models of fork rescue via repriming of the leading strand and a recombinational repair reaction. (A) A blocking lesion on the leading-strand template can be overcome by a new priming event downstream of the blocking lesion. As described in the text, a nascent RNA synthesized by RNA polymerase could provide a primer (green), as could the DnaG primase in the replisome. All newly synthesized DNA is in red, and the blocking lesion is indicated by the small lightning bolt. (B) A broken replication fork can be reconstituted by homologous recombination. In this model, the broken end undergoes strand invasion to create a D-loop structure, which serves as assembly site for a new rightward facing replisome. Branch migration and Holliday junction resolution can remove the branched connection between the two daughter molecules. All newly synthesized DNA is in red, and the blue arrows indicate one of several possible junction resolution reactions (cleavage of the cross strands followed by religation). pol, Polymerase.

Figure 5.

Models of fork rescue via fork regression. (A) When the replication fork encounters a template lesion (small lightning bolt), fork regression can return the lesion into an environment of simple duplex DNA to facilitate a traditional repair event such as excision repair. (B) In cases in which lagging-strand synthesis extends beyond the site of a lesion on the leading-strand template, fork regression provides an opportunity for a strand switching event in which polymerase extension on the extruded arm (DNA in green) effectively bypasses the lesion so that replication can be completed. This gives the cell another cell division cycle to repair the damage using conventional repair pathways. Fork regression can be resolved either by reversal of fork regression (A,B), nucleolytic digestion of the extruded arm (not shown), or (C) strand invasion of the extruded arm ahead of the replication fork. In this figure, all newly synthesized DNA is in red (except for the green template switch patch).