The DNA damage response to transcription stress

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Abstract

The spatiotemporal control of RNA polymerase II (Pol II)-mediated gene transcription is tightly and intricately regulated. In addition, preservation of the integrity of the DNA template is required so as to ensure unperturbed transcription, particularly since DNA is continually challenged by different types of damaging agents that can form transcription-blocking DNA lesions (TBLs), which impede transcription elongation and cause transcription stress. To overcome the highly cytotoxic effects of TBLs, an intricate cellular response has evolved, in which the transcription-coupled nucleotide excision repair (TC-NER) pathway has a central role in removing TBLs specifically from the transcribed strand. Damage detection by stalling of the transcribing Pol II is highly efficient, but a stalled Pol II complex may create an even bigger problem by interfering with repair of the lesions, and overall with transcription and replication. In this Review, we discuss the effects of different types of DNA damage on Pol II, important concepts of transcription stress, the manner in which TBLs are removed by TC-NER and how different tissues respond to TBLs. We also discuss the role of TBLs in ageing and the complex genotype–phenotype correlations of TC-NER hereditary disorders.

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Fig. 1: Transcription-blocking lesions and overview of DNA damage sensing by RNA polymerase II.
Fig. 2: Transcription-coupled nucleotide excision repair.
Fig. 3: Genotype–phenotype correlations of transcription-coupled nucleotide excision repair disorders.
Fig. 4: DNA-damage-induced transcription regulation.
Fig. 5: The activity of TC-NER and GG-NER depends on cell type and the location of transcription-blocking lesions.

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Acknowledgements

This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. The authors also acknowledge financial support from the Dutch Cancer Society (grants KWF 10506 and KWF 11446); Worldwide Cancer Research (grant 15-1274); the Dutch Organization for Scientific Research, ZonMW TOP (912.12.132), ENW TOP (714.017.003 and TOP.017.010) and Gravitation Cancer Genomics.nl (024.001.028) grants; the National Institutes of Health (NIH)/National Institute on Aging (NIA) (PO1 AG017242); Deutsche Forschungsgemeinschaft (Project 73111208-SFB 829); Dutch Organization for Scientific Research VIDI (864.13.004) and VICI (VI.C.182.025) grants to J.M.; European Research Council Advanced Grants to J.H.J.H. (233424 ‘DamAge’ and 742426 ‘Dam2Age’) and W.V. (340988 ‘ERC-ID’); and the Royal Academy of Arts and Sciences of the Netherlands (academia professorship to J.H.J.H.).

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Correspondence to Wim Vermeulen or Jurgen A. Marteijn.

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Glossary

Translesion synthesis

(TLS). DNA polymerization by specialized polymerases past an obstructive DNA modification or damage, which comes at the cost of fidelity and mutagenesis.

R-loops

Three-stranded nucleic acid structures composed of an RNA–DNA hybrid and the complementary single-stranded DNA.

Transcription-blocking DNA lesions

(TBL). Any type of DNA modification, crosslink or damage that strongly impedes or blocks the elongation of RNA polymerases.

Abasic sites

Sites in DNA that lack a purine or pyrimidine base, arising either by spontaneous depurination or by cleavage of the N-glycosidic bond by base excision repair glycosylases.

Cyclobutane pyrimidine dimers

(CPDs). The most frequent type of ultraviolet-induced photolesion; formed by covalent linkage of the C5 and C6 carbon atoms of two adjacent pyrimidines.

Cyclopurines

A form of oxidative DNA damage that is repaired by nucleotide excision repair (NER) but not by base excision repair (BER); cyclopurines are formed by linkage of the C5 carbon atom of 2-deoxyribose and the C8 carbon atom of purine.

Transcription pause sites

Promoter-proximal sites where transcription is stalled, to maintain chromatin open and allow 5′ capping of the nascent RNA, as well as to regulate the timing of transcription.

Oxidative DNA damage

A type of DNA damage formed by oxidation of nucleotides, which is caused mainly by reactive oxygen species. 8-Oxo-2′-deoxyguanosine is the most common type of oxidative DNA lesion.

Base excision repair

(BER). A DNA repair pathway initiated by lesion-specific glycosylases that recognize and remove small base modifications such as oxidative and alkylating DNA lesions.

6–4 pyrimidine–pyrimidone photoproduct

(6–4PP). The second most frequent type of ultraviolet-induced photolesion; formed by covalent linkage of the C4 and C6 carbon atoms of two adjacent pyrimidines.

Progeroid

An adjective to indicate resemblance to accelerated ageing.

XR-seq

Method for sequencing excised oligomers generated during nucleotide excision repair, which allows genome-wide mapping of repair sites.

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