| Summary: | Programmed cell death (PCD) is the result of an intracellular program and is accomplished by a regulated process in both prokaryotic and eukaryotic organisms. Here, we report a programed cell death process in <i>Mycobacterium smegmatis</i>, an Actinobacteria species which involves a transcription factor and a DNase of the HNH family. We found that over-expression of an ArsR family member of the transcription factor, <i>MSMEG_6762,</i> leads to cell death. Transcriptome analysis revealed an increase in the genes’ transcripts involved in DNA repair and homologous recombination, and in three members of HNH family DNases. Knockout of one of the DNase genes, <i>MSMEG_1275</i>, alleviated cell death and its over-expression of programmed cell death. Purified MSMEG_1275 cleaved the <i>M. smegmatis</i> DNA at multiple sites. Overall, our results indicate that the MSMEG_6762 affects cell death and is mediated, at least partially, by activation of the HNH nuclease expression under a stress condition.
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