Chromosome demise in the wake of ligase-deficient replication.

Molecular Microbiology
Elena A Kouzminova, Andrei Kuzminov

Abstract

Bacterial DNA ligases, NAD⁺-dependent enzymes, are distinct from eukaryotic ATP-dependent ligases, representing promising targets for broad-spectrum antimicrobials. Yet, the chromosomal consequences of ligase-deficient DNA replication, during which Okazaki fragments accumulate, are still unclear. Using ligA251(Ts), the strongest ligase mutant of Escherichia coli, we studied ligase-deficient DNA replication by genetic and physical approaches. Here we show that replication without ligase kills after a short resistance period. We found that double-strand break repair via RecA, RecBCD, RuvABC and RecG explains the transient resistance, whereas irreparable chromosomal fragmentation explains subsequent cell death. Remarkably, death is mostly prevented by elimination of linear DNA degradation activity of ExoV, suggesting that non-allelic double-strand breaks behind replication forks precipitate DNA degradation that enlarge them into allelic double-strand gaps. Marker frequency profiling of synchronized replication reveals stalling of ligase-deficient forks with subsequent degradation of the DNA synthesized without ligase. The mechanism that converts unsealed nicks behind replication forks first into repairable double-strand breaks and...Continue Reading

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Citations

Jun 19, 2013·Analytical Biochemistry·Sharik R Khan, Andrei Kuzminov
Aug 22, 2013·Molecular Microbiology·Andrei Kuzminov
Mar 19, 2014·Journal of Bacteriology·Andrei Kuzminov
Feb 13, 2019·Journal of Bacteriology·Sharik R Khan, Andrei Kuzminov
Jan 9, 2019·Proceedings of the National Academy of Sciences of the United States of America·Glen E CronanAndrei Kuzminov
Jun 15, 2018·Microbiology and Molecular Biology Reviews : MMBR·Bénédicte MichelDavid R F Leach

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