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<p><i>Mycobacterium tuberculosis</i> maintains long-term infections characterised by the need to regulate growth and adapt to contrasting in vivo environments. Here we show that <i>M. tuberculosis</i> complex bacteria utilise reversible ADP-ribosylation of single-stranded DNA as a mechanism to coordinate stationary phase growth with transcriptional adaptation. The DNA modification is controlled by DarT, an ADP-ribosyltransferase, which adds ADP-ribose to thymidine, and DarG, which enzymatically removes this base modification. Using <i>darG</i>-knockdown <i>M. bovis</i> BCG, we map the first DNA ADP-ribosylome from any organism. We show that inhibition of replication by DarT is reversible and accompanied by extensive ADP-ribosylation at the origin of replication (OriC). In addition, we observe ADP-ribosylation across the genome and demonstrate that ADP-ribose-thymidine alters the transcriptional activity of <i>M. tuberculosis</i> RNA polymerase. Furthermore, we demonstrate that during stationary phase, DarT-dependent ADP-ribosylation of <i>M. tuberculosis</i> DNA is required to optimally induce expression of the Zur regulon, including the ESX-3 secretion system and multiple alternative ribosome proteins. Thus, ADP-ribosylation of DNA can provide a mechanistic link through every aspect of DNA biology from replication to transcription to translation.</p>

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Control of replication and gene expression by ADP-ribosylation of DNA in Mycobacterium tuberculosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月8日

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  • Rachel E Butler,
  • Marion Schuller,
  • Ritu Jaiswal,
  • Jayanta Mukhopadhyay,
  • Jim Barber,
  • Suzie Hingley-Wilson,
  • Emily Wasson,
  • Alexassander Couto Alves,
  • Ivan Ahel,
  • Graham R Stewart

摘要

Mycobacterium tuberculosis maintains long-term infections characterised by the need to regulate growth and adapt to contrasting in vivo environments. Here we show that M. tuberculosis complex bacteria utilise reversible ADP-ribosylation of single-stranded DNA as a mechanism to coordinate stationary phase growth with transcriptional adaptation. The DNA modification is controlled by DarT, an ADP-ribosyltransferase, which adds ADP-ribose to thymidine, and DarG, which enzymatically removes this base modification. Using darG-knockdown M. bovis BCG, we map the first DNA ADP-ribosylome from any organism. We show that inhibition of replication by DarT is reversible and accompanied by extensive ADP-ribosylation at the origin of replication (OriC). In addition, we observe ADP-ribosylation across the genome and demonstrate that ADP-ribose-thymidine alters the transcriptional activity of M. tuberculosis RNA polymerase. Furthermore, we demonstrate that during stationary phase, DarT-dependent ADP-ribosylation of M. tuberculosis DNA is required to optimally induce expression of the Zur regulon, including the ESX-3 secretion system and multiple alternative ribosome proteins. Thus, ADP-ribosylation of DNA can provide a mechanistic link through every aspect of DNA biology from replication to transcription to translation.