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Cited by 1,122DNA Repair MechanismsNuclear Structure and FunctionDNA and Nucleic Acid Chemistry

Molecular mechanism of nucleotide excision repair

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de Laat, W. L., Jaspers, N. G.J., Hoeijmakers, J. H.J.·1999·Genes & Development
DOI 10.1101/gad.13.7.768
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Abstract

From its very beginning, life has faced the fundamental problem that the form in which genetic information is stored is not chemically inert. DNA integrity is challenged by the damaging effect of numerous chemical and physical agents, compromizing its function. To protect this Achilles heel, an intricate network of DNA repair systems has evolved early in evolution. One of these is nucleotide excision repair (NER), a highly versatile and sophisticated DNA damage removal pathway that counteracts the deleterious effects of a multitude of DNA lesions, including major types of damage induced by environmental sources. The most relevant lesions subject to NER are cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs), two major kinds of injury produced by the shortwave UV component of sunlight. In addition, numerous bulky chemical adducts are eliminated by this process. Within the divergent spectrum of NER lesions, significant distortion of the DNA helix appears to be a common denominator. Defects in NER underlie the extreme photosensitivity and predisposition to skin cancer observed with the prototype repair syndrome xeroderma pigmentosum (XP). Seven XP complementation groups have been identified, representing distinct repair genes XPA–G (discussed in detail below). In the last decade, all key NER factors have been cloned and the core of the ‘cut-and-paste’ reaction has been reconstituted in vitro from purified components. Recently, XPC (complexed to hHR23B) has been identified as a DNA-damage sensor and repair-recruitment factor. The general transcription factor complex TFIIH, containing the XPB and XPD helicases, mediates strand separation at the site of the lesion. XPA verifies the damage in an open DNA conformation and is crucial in the assembly of the remainder of the repair machinery. Replication protein A (RPA) stabilizes the opened DNA complex and is involved in positioning the XPG and ERCC1–XPF endonucleases responsible for the DNA incisions around the lesion. After removal of the damagecontaining oligonucleotide, typically 24–32 nucleotides in length, general replication factors fill in the remaining gap and close it. Two modes of NER can be distinguished: repair of lesions over the entire genome, referred to as global genome NER (GG–NER), and repair of transcription-blocking lesions present in transcribed DNA strands, hence called transcription-coupled NER (TC–NER). Most XP groups harbor defects in a common component of both NER subpathways. GG–NER is dependent on the activity of all factors mentioned above, including the GG– NER-specific complex XPC–hHR23B. The rate of repair for GG–NER strongly depends on the type of lesion. For instance, 6-4PPs are removed much faster from the genome than CPDs, probably because of differences in affinity of the damage sensor XPC–hHR23B. In addition, the location (accessibility) of a lesion influences the removal rate in vivo. In TC–NER, damage is detected by the elongating RNA polymerase II complex when it encounters a lesion. Interestingly, a distinct disorder, Cockayne syndrome (CS), is associated with a specific defect in transcription-coupled repair. The identification of two complementation groups (CS-A and CS-B) shows that at least two gene products are specifically needed for fast and efficient repair of transcribed strands. Phenotypically, CS is a very pleiotropic condition characterized by photosensitivity as well as severe neurological, developmental, and premature aging features. Most of these symptoms are not seen even with totally NERdeficient XP patients. The additional symptoms of CS suggest that transcription-coupled repair and/or the CS proteins have functions beyond NER. Also, non-NERspecific lesions (such as oxidative damage) that stall transcription elongation appear to be removed in a transcription-coupled fashion, linking a blocked polymerase to multiple repair pathways. Intriguingly, some XP-B, XP-D, and XP-G patients display CS features combined with XP manifestations. Yet other XP-B and XP-D individuals suffer from the CS-like brittle-hair syndrome trichothiodystrophy (TTD). This clinical conundrum points to additional roles of these NER factors as well. A recent mouse model for TTD has linked mutations in the XPD subunit of the dual functional TFIIH complex with deficiencies in basal transcription underlying at least some of the TTD manifestations. Thus, NER defects are associated with a surprisingly wide clinical heterogeneity due to additional functions of the NER factors involved. 1Corresponding author. E-MAIL Hoeijmakers@gen.fgg.eur.nl; FAX 31 10 408 9468.

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  • Transcription-coupled repair is carried out by RNA polymerase II with CSA and CSB, whereas global genome repair is initiated by hHR23B-XPC, which senses and binds lesions, distorts DNA locally, and recruits other NER factors.

    “Overall, it has been distinguished that RNA pol II with the recruitment of two proteins (i.e., CSA and CSB) proceeds the TCR while hHR23B-XPC complex is the first factor in NER that initiates GGR by sensing and binding lesions, locally distorting the DNA double helix and recruiting the other factors of the system [227].”

    From Molecular Mechanisms of Ultraviolet Radiation‐Induced DNA Damage and Repair (2010) · cites this paper as [227]

  • The mammalian nucleotide excision repair (NER) pathway removes a wide range of chemically and conformationally diverse DNA adducts, including UVR-induced bulky DNA adducts such as cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP).

    “The mammalian nucleotide excision repair (NER) pathway removes a wide range of chemically and conformationally diverse DNA adducts, including ultraviolet radiation (UVR)-induced bulky DNA adducts, e.g., cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproducts (6-4PP) [3].”

    From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [3]

  • XPA stabilizes the bubble and helps position XPF and XPG endonucleases for 5′ and 3′ incisions to excise a 24-32 bp oligonucleotide containing the damaged lesion.

    “XPA stabilizes the bubble and helps in positioning XPF and XPG endonucleases for respective 5′ and 3′ incisions to excise out a 24–32 bp oligonucleotide containing damaged lesion.”

    From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [3]

  • NER can remove many structurally different lesions, including UV-induced CPD and 6-4PP.

    “NER is a versatile DNA repair pathway that can remove a broad range of structurally unrelated lesions including UV-induced bulky DNA adducts cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP) [2].”

    From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [2]

  • XPA stabilizes the bubble and helps position XPF and XPG endonucleases for incisions that excise a 24-32 bp oligonucleotide containing the lesion.

    “XPA stabilizes the bubble and aids in positioning the XPF and XPG endonucleases for respective 5’ and 3’ incisions to excise out a 24-32 bp oligonucleotide containing damaged lesion.”

    From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [2]

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Research works printed but not linked: 2

  1. Hindges, R. and U. Hu ¨bscher. 1997. DNA polymerase delta, an essential enzyme for DNA transactions. Biol. Chem. 378: 345-362.
  2. Hwang, B.J., J.M. Ford, P.C. Hanawalt, and G. Chu. 1999. Ex- pression of the p48 xeroderma pigmentosum gene is p53 de- pendent and is involved in global genome repair. Proc. Natl. Acad. Sci. 96: 424-428.

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Authors
de Laat, W. L., Jaspers, N. G. J., & Hoeijmakers, J. H. J.
Affiliations
Erasmus University Rotterdam (NL)
Corresponding author
Hoeijmakers, J. H.J.
ORCID
Hoeijmakers, J. H.J.
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
1999-04-01
Volume
13
Issue
7
Pages
768-785
ISSN
0890-9369 (ISSN-L)
DOI
10.1101/gad.13.7.768
OpenAlex
W2124227044
Cited by
1,122
References
240
Citations by year
2026: 5 · 2025: 12 · 2024: 14 · 2023: 20 · 2022: 15 · 2021: 24 · 2020: 30 · 2019: 30 · 2018: 34 · 2017: 25 · 2016: 42 · 2015: 41 · 2014: 47 · 2013: 36 · 2012: 45
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
Funders
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • KWF Kankerbestrijding
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
nucleotide excision repair, DNA damage, cyclobutane pyrimidine dimers, 6-4 photoproducts, xeroderma pigmentosum, XPA, XPC, TFIIH, XPD helicase, replication protein A
MeSH terms
DNA Excision Repair Protein ERCC-5, Chromatin, DNA Repair, DNA-Binding Proteins, Endonucleases, Humans, Models, Genetic, Nuclear Proteins, Proteins, Transcription Factors, Ultraviolet Rays, Xeroderma Pigmentosum, Transcription Factors, TFII, Replication Protein A, Transcription Factor TFIIH, Xeroderma Pigmentosum Group A Protein

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