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Understanding nucleotide excision repair and its roles in cancer and ageing

Key Points

  • The versatile nucleotide excision repair (NER) pathway removes helix-distorting DNA damage in a multistep 'cut and patch'-type reaction. Two damage detection subpathways exist: global genomic NER (GG-NER) removes DNA damage anywhere in the genome, and transcription-coupled NER (TC-NER) specifically repairs transcription-blocking lesions in actively transcribed DNA.

  • GG-NER and TC-NER have a remarkable ability to remove a wide variety of structurally unrelated DNA lesions owing to their indirect manner of DNA-damage detection. GG-NER is initiated by the recognition of damage-induced DNA helix distortions, and TC-NER is initiated by stalling of RNA polymerase II (RNA Pol II) at a lesion.

  • Following lesion recognition, the presence of DNA damage is verified, structure-specific endonucleases are recruited to incise the damaged strand on both sides of the lesion and thereby excise the damage along with short flanking sequences. The excised strand is repaired by gap-filling DNA synthesis using the intact complementary strand as a template.

  • The activity of NER proteins is tightly regulated by post-translational modifications. In particular, the DNA-damage recognition steps are extensively regulated by complex ubiquitylation events.

  • Extensive chromatin remodelling facilitates the DNA-damage detection steps of GG-NER and TC-NER, which results in restarting of transcription after repair and restoration of the original chromatin configuration.

  • Processing of lesions during NER results in repair intermediates that can activate the DNA-damage signalling cascade mediated by ATR, which induces phosphorylation and ubiquitylation of histones H2A and H2A.X.

  • NER deficiency is exemplary of the severe consequences of DNA damage. Congenital defects in NER genes cause various human syndromes, which exhibit a wide range of clinical symptoms, including extreme (skin) cancer predisposition, severe neurodevelopmental defects and premature ageing. This clinical heterogeneity can be explained by the diverse lesions repaired by NER, the existence of two NER subpathways and the multifunctionality of several NER proteins. Differences in the fate of lesion-stalled RNA Pol II may explain the extreme heterogeneity of transcription-coupled repair disorders.

Abstract

Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise 'cut and patch'-type reaction. The global genome NER (GG-NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC-NER) removes transcription-blocking lesions to permit unperturbed gene expression, thereby preventing cell death. Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation-sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome. Recent studies have uncovered new aspects of DNA-damage detection by NER, how NER is regulated by extensive post-translational modifications, and the dynamic chromatin interactions that control its efficiency. Based on these findings, a mechanistic model is proposed that explains the complex genotype–phenotype correlations of transcription-coupled repair disorders.

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Figure 1: Nucleotide excision repair.
Figure 2: Roles of ubiquitylation in nucleotide excision repair.
Figure 3: Chromatin dynamics in nucleotide excision repair.
Figure 4: Genotype–phenotype correlations in disorders of nucleotide excision repair: a unifying model.

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Acknowledgements

The authors acknowledge financial support from: the European commission FP7-Health-2008-200880, HEALTH-F2-2010-259893; US National Institutes of Health and National Institute on Ageing (1PO1 AG-17242-02), US National Institute of Environmental Health Sciences (NIEHS) (1UO1 ES011044); the Royal Academy of Arts and Sciences of the Netherlands (academic professorship awarded to J.H.J.H.); European Research Council Advanced Grants to J.H.J.H. and W.V.; a Koningin Wilhelmina Onderzoeksprijs (KWO) grant from the Dutch Cancer Society; Horizon Zenith project funding from the National Genomics Initiative; Earth and Life Sciences TOP grant to J.H.J.H. and Medical Sciences TOP grant to W.V., by the Dutch Science Organization (NWO); and an Erasmus MC fellowship to J.A.M.

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Glossary

Direct reversal

A one-step DNA repair process involving an enzyme that reverts the DNA lesion to the original nucleotides. Examples are 06-methylguanine DNA methyltransferase (MGMT) and photolyases. MGMT specifically transfers the methyl group from guanine methylated at the 06 position to an internal Cys145 residue in MGMT. This causes a structural change in the enzyme that induces its degradation. Photolyases, which are not found in placental mammals, bind to ultraviolet-radiation-induced photoproducts (either cyclobutane–pyrimidine dimers or 6–4 pyrimidine–pyrimidone photoproducts). With the aid of two light-capturing cofactors, photolyases use the energy of visible light to split these dimers into monomers.

Base excision repair

(BER). This pathway removes oxidative and alkylating DNA lesions. Damaged bases are recognized and cut out from the DNA by lesion-specific glycosylases, which is followed by cleavage of the phosphodiester backbone and gap-filling DNA synthesis of one or a few nucleotides of the resulting single-stranded DNA.

Interstrand crosslink repair

A repair pathway that removes DNA bases from complementary strands that are covalently crosslinked. Defects in this pathway cause Fanconi anaemia.

Cyclobutane–pyrimidine dimers

(CPDs). The most common ultraviolet-radiation-induced DNA lesion, which is formed by covalently linking the C5 and C6 carbon atoms of two adjacent pyrimidines.

6–4 pyrimidine–pyrimidone photoproducts

(6–4PPs). The second most common ultraviolet-radiation-induced DNA lesion, formed by a covalent link between the C4 and C6 carbon atoms of two adjacent pyrimidines. This causes a greater distortion of the DNA helix than cyclobutane–pyrimidine dimers (CPDs). It is more efficiently detected and repaired by mammalian global genome nucleotide excision repair than CPDs.

DNA probing

A process in which DNA-binding proteins freely diffuse through the nucleus and detect DNA damage through a repetitive sampling mechanism (that is, transient DNA binding).

DNA scanning

A process in which DNA-binding proteins slide along the DNA over long distances.

UV–DDB

(Ultraviolet radiation–DNA damage-binding protein). A complex formed by the DDB1 and DDB2 proteins, which is part of a larger complex including the CRL (cullin 4A (CUL4A)–regulator of cullins 1 (ROC1) E3 ubiquitin ligase) complex. It has a high affinity for DNA lesions caused by UV radiation and assists XPC-mediated DNA damage recognition during global genome nucleotide excision repair.

CRL

(Cullin 4A (CUL4A)–regulator of cullins 1 (ROC1) E3 ubiquitin ligase). A modular E3 ubiquitin ligase complex consisting of the RING finger protein ROC1 and the CUL4A scaffold protein, which interacts with DNA damage-binding protein 1 (DDB1). Its target specificity is regulated by switching interactions with WD40- domain-containing substrate proteins, such as DDB2 in global genome nucleotide excision repair (GG-NER) and Cockayne syndrome protein CSA in transcription-coupled NER (TC-NER).

WD40 domain

A short structural protein motif with β-propeller architecture that is believed to be involved in protein–protein interactions.

TFIIH

(Transcription initiation factor IIH). An essential transcription initiation complex that is also pivotal for nucleotide excision repair. In both processes it functions to unwind DNA using its two helicase subunits.

CAK subcomplex

(CDK-activating kinase subcomplex). A subcomplex of TFIIH (transcription initiation factor IIH) that consists of cyclin-dependent kinase 7 (CDK7), cyclin H (CCNH) and MNAT1 (also known as MAT1). The CAK subcomplex has an important function in transcription initiation as it phosphorylates the largest subunit of RNA polymerase II, but it is not required for nucleotide excision repair and dissociates from TFIIH.

Damage avoidance

A process that occurs when DNA replication encounters an unrepaired DNA lesion. Such lesions block the regular replication machinery on the damaged strand. However, replication of the undamaged complementary strand can still continue, which generates a daughter strand with the same sequence as the damaged template. The lesion in the original template strand can be bypassed by transiently switching replication to the newly synthesized daughter strand.

Cockayne syndrome

A human disorder characterized by ultraviolet radiation sensitivity, progeria, and neurological and developmental abnormalities. The syndrome is caused by mutations in several genes encoding proteins involved in transcription-coupled nucleotide excision repair (TC-NER).

Oxidative DNA damage

A large group of DNA lesions that are mainly caused by reactive oxygen species (ROS) that oxidize nucleotides at several positions. Oxidative DNA lesions are unavoidable, as ROS are natural products of cellular metabolism and the immune system, or are formed by environmental chemicals and radiation.

Poly(ADP-ribosyl)ation

(PARylation). The polymerization of ADP–ribose units from donor NAD+ molecules on target proteins by enzymes of the poly(ADP-ribosyl) polymerase (PARP) family. PARP enzymes detect single-strand breaks in DNA and regulate the efficiency of several lesion repair mechanisms by PARylation of damaged chromatin and signalling proteins.

COP9 signalosome

A multisubunit protease that regulates the activity of CRL (cullin 4A (CUL4A)–regulator of cullins 1 (ROC1) E3 ubiquitin ligase) complexes by removing the ubiquitin-like protein NEDD8.

Chromatin remodelling

Dynamic alteration of the chromatin structure to regulate access of proteins to DNA, which is induced by post-translational modifications of histone tails and ATP-dependent remodelling complexes that move or restructure nucleosomes.

Xeroderma pigmentosum

A human disorder caused by defects in genes that encode proteins involved in global genome nucleotide excision repair (GG-NER). It is characterized by ultraviolet radiation hypersensitivity and an increased risk of skin cancer and internal tumours.

Xeroderma pigmentosum complementation group

Cells from patients with xeroderma pigmentosum are classified into eight genetic complementation groups (XP-A to XP-G and XP-Variant), which are based on their respective gene and protein defects.

De Sanctis–Cacchione syndrome

A severe and rare form of xeroderma pigmentosum in which patients display accelerated neurodegeneration, microcephaly, retarded growth and impaired sexual development.

Illudin S

A natural (mushroom-derived) sesquiterpene drug, which causes DNA lesions that block replication and transcription. These lesions are repaired by transcription-coupled nucleotide excision repair (TC-NER) but ignored by global genome nucleotide excision repair (GG-NER).

Progeroid phenotype

A phenotype of accelerated ageing that is exhibited by patients at a young age.

Cerebro-oculo-facio-skeletal syndrome

(COFS). A very severe human disorder resembling Cockayne syndrome. It involves the neurological system, eyes, face, and skeleton, and results in a very short life expectancy of 2–3 years. It is caused by severe mutations in genes encoding proteins involved in transcription-coupled nucleotide excision repair as well as in several other DNA repair processes.

Single-strand annealing

An error-prone mechanism that repairs double-strand breaks situated between two repetitive DNA sequences. It functions by resecting the broken ends, which is followed by homologous pairing of the repeats, gap-filling DNA synthesis and ligation. The sequences between the repeats are lost as the consequence of this process.

UV-sensitive syndrome

(UVSS). A human disorder characterized by mild ultraviolet radiation sensitivity of the skin. It is caused by inactivating mutations in the UVSSA gene (which encodes UV-stimulated scaffold protein A) and specific mutations in the genes encoding Cockayne syndrome proteins CSA and CSB, which are involved in transcription-coupled nucleotide excision repair (TC-NER).

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Marteijn, J., Lans, H., Vermeulen, W. et al. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol 15, 465–481 (2014). https://doi.org/10.1038/nrm3822

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