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Transcription

Mechanisms of transcription-coupled DNA repair

Nature Reviews Molecular Cell Biology volume 3, pages 21–29 (2002)Cite this article

Key Points

  • Transcription-coupled repair (TCR) — the fast, preferential repair of the transcribed strand of an active gene — occurs in both prokaryotes and eukaryotes. This kind of repair is performed by the nucleotide excision repair (NER) or the base excision repair (BER) pathways.

  • Different factors allow the repair machinery to be specifically targetted to the transcribed strand and the global genome, respectively. The best-studied TCR factors are CSA and CSB (yeast Rad26), but factors such as XPG and TFIIH also have a role.

  • Cells respond to DNA damage by globally downregulating transcription. This might be brought about by several mechanisms working concomitantly.

  • TCR is triggered by the stalled polymerase itself. In the promoter of an active gene, repair is slow. TCR is extra fast immediately downstream from the transcription initiation site, presumably because TFIIH is still associated with the polymerase at this point.

  • Nucleosomes are inhibitory to NER on the non-transcribed strand (repair being slower towards the cores), whereas the speed of TCR is not affected by the presence of the same nucleosomes.

  • In the transcribed strand, RNA polymerase II (RNAPII) is an obstacle to TCR and Rad26/CSB is required to overcome this obstacle to fast repair.

  • Several models for the mechanism of TCR have been proposed, and they all incorporate some sort of displacement of RNAPII from the site of DNA damage.

  • Although much has been learned about the factors and processes affecting TCR, much still needs to be learned about the precise molecular mechanism of the reaction.

Abstract

Several types of helix-distorting DNA lesions block the passage of elongating RNA polymerase II. Surprisingly, such transcription-blocking lesions are usually repaired considerably faster than non-obstructive lesions in the non-transcribed strand or in the genome overall. In this review, our knowledge of eukaryotic transcription-coupled repair (TCR) will be considered from the point of view of transcription, and current models for the mechanism of TCR will be discussed.

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Figure 1: Mechanism of nucleotide excision repair and base excision repair.
Figure 2: Models for the mechanism of transcriptional downregulation in response to DNA damage.
Figure 3: Speed of repair in an active gene.
Figure 4: Models for transcription-coupled repair.

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Acknowledgements

Work relevant to this review was supported by an in-house grant from the Imperial Cancer Research Fund. T. Lindahl and B. Winkler are thanked for their comments and suggestions.

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Authors and Affiliations

  1. Imperial Cancer Research Fund, Clare Hall Laboratories, Blanche Lane, South Mimms, EN6 3LD, Hertfordshire, UK

    Jesper Q. Svejstrup

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  1. Jesper Q. Svejstrup
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DATABASES

Encyclopedia of Life Sciences:

DNA-repair-deficiency disorders

 OMIM:

trichothiodystrophy

XPA

XPF

XPG

 Saccharomyces Genome Database:

Rad1

Rad2

Rad3

Rad4

RAD7

Rad10

Rad14

RAD16

Rad23

Rad25

RAD26

RAD28

Rsp5

Spt4

URA3

 Swiss-Prot:

CSA

DDB2

ERCC1

FEN1

HHR23B

RPB1

T4 endonuclease V

XAB2

XPA

XPB

XPC

XPD

XPF

XPG

FURTHER READING

Human DNA repair genes

Glossary

DNA LIGASE

Seals DNA breaks containing a 5′-phosphorylated end and a 3′-OH end. Several different DNA ligases are found in eukaryotic cells.

TFIIH

(Transcription factor IIH). One of the factors that are generally required for RNA polymerase II-dependent transcription. Also has an essential role in nucleotide excision repair.

HELICASE

An enzyme that uses the energy of ATP hydrolysis to unwind/separate the two strands of DNA.

ENDONUCLEASE

Cuts DNA internally. Often, but not always, cuts at specific recognition sequences.

DNA GLYCOSYLASE

Binds specifically to a target base and hydrolyses the N-glycosylic bond. This releases the inappropriate base while keeping the DNA backbone intact. Several distinct glycosylases exist in eukaryotic cells.

ABASIC SITE

A nucleotide site that has lost the base.

'FLAP' ENDONUCLEASE

A structure-specific endonuclease, which cleaves off a single-stranded piece of DNA that is not base-paired owing to, for example, mismatched bases.

SNF2 PROTEIN FAMILY

A family of proteins that have helicase-like ATPase domains, yet are not helicases. Rather than unwinding DNA strands, these proteins remodel protein–DNA contacts, such as histone–DNA contacts.

SWI/SNF-LIKE COMPLEXES

Protein complexes that contain a subunit that is homologous to SNF2.

WD40 REPEAT

A protein motif used by a variety of proteins for protein–protein interactions.

ORTHOLOGUE

A homologue whose sequence and function has been conserved during evolution.

RING FINGER

Protein motif that is found in ubiquitin ligases.

RAD7 AND RAD16

Proteins that are required for global genome repair in yeast. They are very important for nucleotide excision repair of the non-transcribed strand of an active gene, but have only a minor role for repair on the transcribed strand/transcription-coupled repair.

NON-HOMOLOGOUS END-JOINING

Repair pathway in which severed DNA ends are re-joined. The prominent pathway for repairing double-stranded breaks in higher eukaryotic cells.

HYPOPHOSPHORYLATED RNAPII A-FORM

The carboxy-terminal domain (CTD) of the largest RNAPII subunit comprises 26–52 heptapeptide repeats (consensus Tyr-Ser-Pro-Thr-Ser-Pro-Ser). The RNAPII form that is hypophosphorylated on the CTD is called RNAPII-A, whereas the form that is multiply phosphorylated (hyperphosphorylated) on Ser2 and Ser5 of the repeat is called RNAPII-0.

TATA-BINDING PROTEIN

The TATA-binding protein (TBP) binds directly to the TATA sequence in the core promoter of a gene to initiate assembly of the general transcription factor machinery that enables RNAPII to transcribe the gene.

UBIQUITYLATION

The covalent linkage of the small protein ubiquitin to other proteins is essential for a variety of cellular processes. Ubiquitylation can mark proteins for rapid intracellular degradation, but can also have other consequences for the modified substrate protein.

UBIQUITIN LIGASE

The last enzyme in a cascade of ubiquitin-mobilizing proteins that together enable ubiquitylation. First, ubiquitin is activated by formation of a thioester bond to a ubiquitin- activating enzyme (E1). After transfer to a ubiquitin- conjugating enzyme (E2), ubiquitin is ligated to a protein substrate with the help of a ubiquitin protein ligase (E3). Several ubiquitin moieties can be added to the substrate, each time forming an isopeptide bond to an internal lysine residue.

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Svejstrup, J. Mechanisms of transcription-coupled DNA repair. Nat Rev Mol Cell Biol 3, 21–29 (2002). https://doi.org/10.1038/nrm703

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