期刊
NATURE REVIEWS MOLECULAR CELL BIOLOGY
卷 20, 期 12, 页码 766-784出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41580-019-0169-4
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资金
- Dutch Cancer Society
- Dutch Cancer Society [KWF 10506, KWF 11446]
- Worldwide Cancer Research [15-1274]
- Dutch Organization for Scientific Research, ZonMW TOP grant [912.12.132]
- Dutch Organization for Scientific Research, ENW TOP grant [714.017.003, TOP.017.010]
- Dutch Organization for Scientific Research, Gravitation Cancer Genomics.nl grant [024.001.028]
- National Institutes of Health (NIH)/National Institute on Aging (NIA) [PO1 AG017242]
- Deutsche Forschungsgemeinschaft [73111208-SFB 829]
- European Research Council Advanced Grants [233424, 742426, 340988]
- Royal Academy of Arts and Sciences of the Netherlands
- Dutch Organization for Scientific Research VIDI grant [864.13.004]
- Dutch Organization for Scientific Research VICI grant [VI.C.182.025]
- European Research Council (ERC) [340988, 742426, 233424] Funding Source: European Research Council (ERC)
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 PollI 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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