Crucial role and mechanism of transcription-coupled DNA repair in bacteria

Binod K. Bharati, Manjunath Gowder, Fangfang Zheng, Khaled Alzoubi, Vladimir Svetlov, Venu Kamarthapu, Jacob W. Weaver, Vitaly Epshtein, Nikita Vasilyev, Liqiang Shen, Yu Zhang () and Evgeny Nudler ()
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Binod K. Bharati: New York University School of Medicine
Manjunath Gowder: New York University School of Medicine
Fangfang Zheng: Chinese Academy of Sciences
Khaled Alzoubi: New York University School of Medicine
Vladimir Svetlov: New York University School of Medicine
Venu Kamarthapu: New York University School of Medicine
Jacob W. Weaver: New York University School of Medicine
Vitaly Epshtein: New York University School of Medicine
Nikita Vasilyev: New York University School of Medicine
Liqiang Shen: Chinese Academy of Sciences
Yu Zhang: Chinese Academy of Sciences
Evgeny Nudler: New York University School of Medicine

Nature, 2022, vol. 604, issue 7904, 152-159

Abstract: Abstract Transcription-coupled DNA repair (TCR) is presumed to be a minor sub-pathway of nucleotide excision repair (NER) in bacteria. Global genomic repair is thought to perform the bulk of repair independently of transcription. TCR is also believed to be mediated exclusively by Mfd—a DNA translocase of a marginal NER phenotype1–3. Here we combined in cellulo cross-linking mass spectrometry with structural, biochemical and genetic approaches to map the interactions within the TCR complex (TCRC) and to determine the actual sequence of events that leads to NER in vivo. We show that RNA polymerase (RNAP) serves as the primary sensor of DNA damage and acts as a platform for the recruitment of NER enzymes. UvrA and UvrD associate with RNAP continuously, forming a surveillance pre-TCRC. In response to DNA damage, pre-TCRC recruits a second UvrD monomer to form a helicase-competent UvrD dimer that promotes backtracking of the TCRC. The weakening of UvrD–RNAP interactions renders cells sensitive to genotoxic stress. TCRC then recruits a second UvrA molecule and UvrB to initiate the repair process. Contrary to the conventional view, we show that TCR accounts for the vast majority of chromosomal repair events; that is, TCR thoroughly dominates over global genomic repair. We also show that TCR is largely independent of Mfd. We propose that Mfd has an indirect role in this process: it participates in removing obstructive RNAPs in front of TCRCs and also in recovering TCRCs from backtracking after repair has been completed.

Date: 2022
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DOI: 10.1038/s41586-022-04530-6

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