Shining a light on xeroderma pigmentosum
Open accessAbstract
Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair characterized by sun sensitivity and UV radiation-induced skin and mucous membrane cancers. Initially described in 1874 by Moriz Kaposi in Vienna, nearly 100 years later, James Cleaver in San Francisco reported defective DNA repair in XP cells. This eventually provided the basis for a mechanistic link between sun exposure, DNA damage, somatic mutations, and skin cancer. XP cells were found to have defects in seven of the proteins of the nucleotide excision repair pathway and in DNA polymerase η. XP cells are hypersensitive to killing by UV radiation, and XP cancers have characteristic "UV signature" mutations. Clinical studies at the National Institutes of Health found a nearly 10,000-fold increase in skin cancer in XP patients under the age of 20 years, demonstrating the substantial importance of DNA repair in cancer prevention in the general population. Approximately 25% of XP patients have progressive neurological degeneration with progressive loss of neurons, probably from DNA damage induced by oxidative metabolism, which kills nondividing cells in the nervous system. Interestingly, patients with another disorder, trichothiodystrophy, have defects in some of the same genes as XP, but they have primary developmental abnormalities without an increase in skin cancer.
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XP patients under the age of 20 years show a 10,000-fold increase in skin cancer, demonstrating the substantial importance of DNA repair in cancer prevention in the general population.
“Specifically, XP patients under the age of 20 years show a 10,000-fold increase in skin cancer, which demonstrates the substantial importance of DNA repair in cancer prevention in the general population [203][204][205].”
From Sunlight damage to cellular DNA: focus on oxidatively generated lesions (2017) · cites this paper as [205]
Most xeroderma pigmentosum complementation groups A-G have a high incidence of skin tumors and deficiencies in nucleotide excision repair.
“Another indirect evidence for the implication of photoinduced damage to DNA in carcinogenicity is provided by the high incidence of skin tumors in most of the complementation groups A-G of xeroderma pigmentosum patients (17,18) who suffer from deficiencies in nucleotide excision repair (19).”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [18]
XP patients, especially those with XPA deficiency, often suffer neurological deficiencies and an early-aging phenotype.
“In addition to high dermatological sensitivity to sunlight XP patients, especially those with an XPA deficiency, often suffer from neurological deficiencies and an early-aging phenotype 2,”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [2]
The neurological and early-aging features of XPA deficiency are likely due to non-NER mechanisms.
“likely due to non-NER mechanisms as exogenous, genotoxin-induced bulky adducts would not be a concern.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [2]
NER is important for resistance to UV-induced cancers, as shown by XP patients with homozygous NER defects who are profoundly predisposed to melanoma and other UV-induced skin cancers.
“The importance of NER in resistance to UV-induced cancers is clearly demonstrated by observing the natural history of xeroderma pigmentosum (XP) patients, who through homozygous loss of one of the enzymes that carry out NER, are profoundly predisposed to melanoma and other UV-induced skin cancers”
From RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage (2014) · cites this paper as DiGiovanna and Kraemer, 2012
Photolesions are repaired by NER, a multistep process involving XPA, ERCC1, ERCC3, XPC, ERCC2, DDB2, ERCC4, and ERCC5.
“Photolesions engage the nucleotide excision repair (NER) pathway, which corrects UV-induced DNA damage in a multistep process involving numerous repair factors including XPA, ERCC1, ERCC3 (XP-B), XPC, ERCC2 (XP-D), DDB2 (XP-E), ERCC4 (XP-F) and ERCC5 (XP-G)”
From RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage (2014) · cites this paper as DiGiovanna and Kraemer, 2012
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DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease
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Jarrett, S. G., Wolf Horrell, E. M., Boulanger, M. C., & D'Orazio, J. A. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.280 · Cited by 54 · see citing works
Care of the newborn with ichthyosis
Dyer, J. A., Spraker, M. K., & Williams, M. L. K. (2013) · Dermatologic Therapy · doi:10.1111/j.1529-8019.2012.01555.x · Cited by 54 · see citing works
IRF4, MC1R and TYR genes are risk factors for actinic keratosis independent of skin color
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A Distinct Triplex DNA Unwinding Activity of ChlR1 Helicase
Guo, M., Hundseth, K., Ding, H., Vidhyasagar, V., Inoue, A., Nguyen, C.-H., Zain, R., Lee, J. S., & Wu, Y. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.634923 · Cited by 53 · see citing works
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Self-citationDNA damage mediated transcription arrest: Step back to go forward
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Self-citationAutophagy and mitophagy interplay in melanoma progression
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Keratoacanthoma: a distinct entity?
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A key interaction with RPA orients XPA in NER complexes
Topolska‐Woś, A. M., Sugitani, N., Cordoba, J. J., Meur, K. V. L., Meur, R. A. L., Kim, H. S., Yeo, J.-E., Rosenberg, D. J., Hammel, M., Schärer, O. D., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1231 · Cited by 47 · see citing works
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- Authors
- DiGiovanna, J. J., & Kraemer, K. H.
- Affiliations
- National Cancer Institute (US)
- Corresponding author
- Kraemer, Kenneth H.
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 132
- Issue
- 3
- Pages
- 785-796
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC3279615
- OpenAlex
- W2082139407
- Cited by
- 547
- References
- 98
- Citations by year
- 2026: 22 · 2025: 21 · 2024: 31 · 2023: 32 · 2022: 38 · 2021: 42 · 2020: 36 · 2019: 46 · 2018: 39 · 2017: 51 · 2016: 39 · 2015: 40 · 2014: 52 · 2013: 40 · 2012: 16
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (ZIABC004517)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- xeroderma pigmentosum, DNA repair, nucleotide excision repair, UV-induced skin cancer, sun sensitivity, neurodegeneration, trichothiodystrophy, cancer prevention
- MeSH terms
- DNA Repair, Humans, Skin Neoplasms, Sunlight, Xeroderma Pigmentosum
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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