Thymineless death is associated with loss of essential genetic information from the replication origin

• Published in: Molecular microbiology Vol. 75; no. 6; pp. 1455 - 1467
• Main Authors: Sangurdekar, Dipen P, Hamann, Bree L, Smirnov, Dmitri, Srienc, Friedrich, Hanawalt, Philip C, Khodursky, Arkady B
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.03.2010; Blackwell Publishing Ltd; Blackwell
• Subjects: Apoptosis; Biological and medical sciences; Cell Death; Cells; Chromosomes, Bacterial - genetics; Chromosomes, Bacterial - metabolism; DNA Damage; DNA repair; DNA Replication; DNA, Bacterial - genetics; DNA, Bacterial - metabolism; E coli; Escherichia coli; Escherichia coli - genetics; Escherichia coli - metabolism; Fundamental and applied biological sciences. Psychology; Microbial Viability; Microbiology; Mutation; Replication Origin - genetics; Thymine - metabolism; Origin; Genetics; Replication
• DOI: 10.1111/j.1365-2958.2010.07072.x
• ISSN: 0950-382X

Thymine starvation results in a terminal cellular condition known as thymineless death (TLD), which is the basis of action for several common antibiotics and anticancer drugs. We characterized the onset and progression of TLD in Escherichia coli and found that DNA damage is the only salient property that distinguishes cells irreversibly senesced under thymine starvation from cells reversibly arrested by the nucleotide limitation. The damage is manifested as the relative loss of genetic material spreading outward from the replication origin: the extent of TLD correlates with the progression of damage. The reduced lethality in mutants deficient in the RecFOR/JQ repair pathway also correlates with the extent of damage, which explains most of the observed variance in cell killing. We propose that such spatially localized and persistent DNA damage is the consequence of transcription-dependent initiation of replication in the thymine-starved cells and may be the underlying cause of TLD.