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Transcription-coupled DNA repair: two decades of progress and surprises

Key Points

  • Expressed genes are scanned by translocating RNA polymerases, which can sensitively detect DNA damage and initiate the dedicated pathway of transcription-coupled repair (TCR).

  • TCR is a subpathway of the ubiquitous process of nucleotide excision repair; it removes lesions from the template DNA strands of actively transcribed genes. TCR is superimposed on the global genomic subpathway of nucleotide excision repair, which removes DNA damage throughout the genome.

  • The most prevalent human hereditary disease that exhibits DNA-repair deficiency is xeroderma pigmentosum, which is characterized by severe sunlight sensitivity and a high predisposition to cancer in sun-exposed parts of the body. A variant form of the disease is caused by a deficiency in a translesion DNA polymerase. By contrast, in hereditary diseases that present a deficiency only in TCR, severe sunlight sensitivity is not accompanied by enhanced skin cancer.

  • Although the mechanism of TCR is well understood in bacteria, there are several possible scenarios for the pathway following RNA polymerase arrest in eukaryotes and mammalian cells in particular.

  • Multiple gene products are implicated in TCR, but we still do not understand the precise signals that can trigger this pathway. Such understanding might lead to novel modes of cancer chemotherapy, involving selective inhibition of TCR in target cells combined with administration of transcription-blocking drugs.

  • Futile cycles of TCR might be initiated at naturally occurring non-canonical DNA structures and could contribute to genomic instability and genetic disease.

Abstract

Expressed genes are scanned by translocating RNA polymerases, which sensitively detect DNA damage and initiate transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes lesions from the template DNA strands of actively transcribed genes. Human hereditary diseases that present a deficiency only in TCR are characterized by sunlight sensitivity without enhanced skin cancer. Although multiple gene products are implicated in TCR, we still lack an understanding of the precise signals that can trigger this pathway. Futile cycles of TCR at naturally occurring non-canonical DNA structures might contribute to genomic instability and genetic disease.

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Figure 1: The stepwise pathway for bacterial TCR and GGR.
Figure 2: Probable sequence of events in mammalian TCR and GGR.
Figure 3: Potential outcomes following RNAPII arrest.
Figure 4: A suggested scenario for initiation of repair through TCR.

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Acknowledgements

The authors thank A. Ganesan and C. A. Smith for helpful discussions, and the National Cancer Institute for research support.

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Correspondence to Philip C. Hanawalt.

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DATABASES

OMIM

Bloom syndrome

Cockayne syndrome

Rothmund–Thomson syndrome

trichothiodystrophy

UV-sensitive syndrome

Werner syndrome

FURTHER INFORMATION

Philip C. Hanawalt's laboratory

DNA Repair Interest Group

HUGO

Human DNA repair genes

NIA Mouse Gene Index

Glossary

Translesion synthesis

The continuity of replication (or transcription) through a damaged site in the DNA template, in general with a high probability of errors that can lead to mutation.

Transcription-coupled repair

The specialized repair pathway that operates on lesions in the transcribed strands of expressed genes.

Nucleotide excision repair

The classic process by which a large range of structurally unrelated alterations in duplex DNA can be repaired. Following lesion recognition, incisions are made on both sides of the lesion and a short stretch of the DNA strand that contains the damage is excised. A repair patch is synthesized using the undamaged complementary DNA strand as a template.

Global genomic repair

DNA repair throughout the genome, without distinguishing between sequence, activity or chromatin structure.

Non-B form DNA structure

A DNA secondary structure that differs from the canonical Watson–Crick right-handed double helix of ten bases per turn of the helix. Examples include left-handed Z-DNA, triple-stranded H-DNA and four-stranded quadruplex DNA.

α-DNA

A highly repetitive DNA sequence that is found near centromeres in chromosomes from primates.

Cyclobutane pyrimidine dimer

The principal photoproduct that is formed in DNA following absorption of short-wavelength ultraviolet light. Adjacent pyrimidines are covalently linked through their C-5 and C-6 carbon atoms.

6–4 photoproduct

An ultravioletinduced DNA lesion formed between the C-4 position of a 5′ pyrimidine and the C-6 position of an adjacent pyrimidine. This occurs approximately one-third as frequently as the cyclobutane pyrimidine dimer, but causes greater structural distortion.

SOS genomic stress response

A bacterial response to replication arrest, regulated by RecA and LexA proteins, to upregulate over 40 genes that control nucleotide excision repair, translesion DNA synthesis, recombination and other functions, such as cell division.

G4 quadruplex DNA

Planar guanine-quartet structures that are formed by DNA strands with repeats of three or more consecutive guanines. In the mammalian genome, these repeats are found in telomeres, ribosomal DNA and in genes for the immunoglobulin heavy chain segments.

Base excision repair

An excision repair pathway that is initiated by a glycosylase to remove a damaged or inappropriate base, leaving an abasic site. In the second step, the phosphodiester backbone is cleaved and a short patch (one nucleotide or more) is synthesized and ligated to the contiguous DNA.

Adduct

A covalently bound chemical residue, such as a methyl group or cisplatin, to a base or nucleotide in DNA. In some cases, the chemical binds more than one nucleotide, forming intrastrand or interstrand crosslinks.

Abasic site

A common form of DNA damage that is caused by the spontaneous loss of a base or an intermediate in the base excision repair pathway. This follows the removal of a base by glycosylase, while leaving the phosphodiester bond intact.

Z-DNA

A non-canonical form of DNA that can occur in stretches of alternating guanine and cytosine bases, in which the strands are wound in a left-handed manner, to form a zigzag backbone structure.

Triplet nucleotide repeat expansions

The phenomenon that is characteristic in over a dozen human genetic diseases, in which massive expansions occur in a particular genomic region of repetitive nucleotide triplets, such as CAG in the case of Friedreich's ataxia.

RecQ-family helicase

One of a family of evolutionarily conserved helicases that were first discovered in Escherichia coli. Mutations in three of the five RecQ homologues in humans can cause cancer predisposition and/or premature ageing, such as in Werner's syndrome.

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Hanawalt, P., Spivak, G. Transcription-coupled DNA repair: two decades of progress and surprises. Nat Rev Mol Cell Biol 9, 958–970 (2008). https://doi.org/10.1038/nrm2549

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