Review
doi: 10.1111/php.12661. Epub 2016 Dec 27.From Mfd to TRCF and Back Again-A Perspective on Bacterial Transcription-coupled Nucleotide Excision Repair
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- PMID:27859304
- PMCID: PMC5672955
- DOI: 10.1111/php.12661
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Review
From Mfd to TRCF and Back Again-A Perspective on Bacterial Transcription-coupled Nucleotide Excision Repair
Alexandra M Deaconescu et al. Photochem Photobiol.2017 Jan.
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Abstract
Photochemical and other reactions on DNA cause damage and corrupt genetic information. To counteract this damage, organisms have evolved intricate repair mechanisms that often crosstalk with other DNA-based processes such as transcription. Intriguing observations in the late 1980s and early 1990s led to the discovery of transcription-coupled repair (TCR), a subpathway of nucleotide excision repair. TCR, found in all domains of life, prioritizes for repair lesions located in the transcribed DNA strand, directly read by RNA polymerase. Here, we give a historical overview of developments in the field of bacterial TCR, starting from the pioneering work of Evelyn Witkin and Aziz Sancar, which led to the identification of the first transcription-repair coupling factor (the Mfd protein), to recent studies that have uncovered alternative TCR pathways and regulators.
© 2016 The American Society of Photobiology.
Figures
A timeline of key developments in the TCR field.
(a) In the canonical model, Mfd binds upstream of the RNAP stalled by a lesion (purple star) and translocates in the 3′ to 5′ direction with respect to the transcribed strand. This translocation activity serves to ‘push’ RNAP forward resulting in reannealing of the upstream edge of the transcription bubble and unwinding the RNA/DNA hybrid to dissociate stalled transcription elongation complexes. Mfd likely remains associated with the lesion to recruit the NER machinery through direct interaction with UvrA. TCR joins general the NER pathway at the damage verification step. (b) In the lesion-sensing (repair at a distance) model, Mfd (in complex with a RNAP that has been displaced from the nucleic acid chains) scans downstream from an RNAP pause site (orange sequence) until it reaches a lesion. It then recruits the NER machinery and joins general NER at the damage verification step.
a) Schematic representation of Mfd domain architecture colored as follows: D1a in blue, D2 in cyan, D1b in slate, D3 in orange, RID in magenta, D5 in yellow, D6 in green, and D7 in red. The horizontal bar represents the 1148-residue primary sequence with colored blocks indicating domains and black lines highlighting flexible connecting linkers. b) Top and side views showing an α carbon backbone ribbon representation of theE. coli apo Mfd structure (PDB ID 2EYQ) with domains colored as in (a). Top inset shows an α carbon ribbon representation ofThermus sp. core Mfd-RID/RNAP-β complex (PDB ID 3MLQ). Bottom inset shows an α carbon representation ofE. coli core Mfd/UvrA complex (PDB ID 4DFC). c) Overall architecture ofThermus thermophilus RNAP elongation complex (PDB ID 2O5I) with RNAP subunits colored as follows: α1 and α2 in orange and yellow, β in cyan, β′ in pink, ω in red. The N-terminal region of the β subunit interacting with Mfd-RID is colored in deep teal. Residues involved in direct contacts with Mfd-RID (the “IKE” motif) are shown as green spheres (β subunit I108, K109, and E110). Residues involved in direct contacts with UvrD are shown as purple spheres (β subunit K781, β′ subunit K28 and R67). d) Overall architecture ofThermus aquaticus transcription initiation complex bound to CarD (PDB ID 4XLS). RNAP subunits are colored as in (c) and the σ factor in gray. The CarD-RID is magenta and CarD-CTD is green.
UvrD and NusA associate with RNAP throughout transcription elongation. Upon induction of the DNA damage response the concentration of UvrD increases (113, 114) resulting in UvrD dimerization and activation of its helicase activity. With the help of NusA, UvrD pushes RNAP backwards without collapsing the transcription bubble possibly using its helicase activity to unwind the upstream edge of the bubble. As with the Mfd-dependent TCR pathway, UvrD-dependent TCR joins general NER at the damage verification step. However, transcription elongation can resume after UvrD-dependent TCR with the assistance of anti-backtracking factors.
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