Abstract
Thymineless death (TLD) in bacteria has been a focus of research for decades. Nevertheless, the advances in the last 5 years, with Escherichia coli as the model organism, have been outstanding. Independent research groups have presented compelling results that establish that the initiation of chromosome replication under thymine starvation is a key element in the scenario of TLD. Here we review the experimental results linking the initiation of replication to the lethality under thymine starvation and the proposed mechanisms by which TLD occurs. The concept of this relationship was ‘in the air,’ but approaches were not sufficiently developed to demonstrate the crucial role of DNA initiation in TLD. Genome-wide marker frequency analysis and Two Dimensional agarose gel electrophoresis have been critical methods employed to reveal that initiation events and the degradation of the oriC region occur during thymine starvation. The relationships between these events and TLD have established them to be the main underlying causes of the lethality under thymine starvation. Furthermore, we summarize additional important findings from the study of different mutant strains, which support the idea that the initiation of chromosomal replication and TLD are connected.
Highlights
Thymineless death (TLD) is defined by the loss of viability that occurs in a culture of a thyA defective mutant strain when deprived of thymine (Figure 1A)
The relevance of these results relies on the fact that TLD alleviation in these mutants must be related to the alteration of the normal transcription levels around oriC. This effect on TLD, combined with the broad reduction in chromosome initiation intermediates in these mutants (Figure 2C), strongly suggests that the transcriptiondependent step of the initiation is the target for rifampicin suppression of TLD, being critical for TLD. These experimental approaches pinpoint the initiations at the oriC region as the main targets for TLD in wild type strains
If DNA initiation is allowed under thymine starvation, death occurs likely due to the lethal consequences of the presence of double strand breaks (DSBs), DNAss gaps, and DNA recombination intermediates at the origin that eventually result in oriC region degradation
Summary
Thymineless death (TLD) is defined by the loss of viability that occurs in a culture of a thyA defective mutant strain when deprived of thymine (Figure 1A). It was first reported by Barner and Cohen 60 years ago (Barner and Cohen, 1954). Abortive events in attempted initiation during thymine starvation may be associated with the observed degradation of the oriC DNA sequence that eventually leads to TLD.
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