Global Contributions to the Understanding of DNA Repair and Skin Cancer
2014; Elsevier BV; Volume: 134; Linguagem: Inglês
10.1038/skinbio.2014.3
ISSN1523-1747
AutoresKenneth H. Kraemer, John J. DiGiovanna,
Tópico(s)CRISPR and Genetic Engineering
ResumoLiving organisms exposed to sunlight have developed mechanisms to repair the damage that UVR induces in their DNA. These DNA repair systems are present in most life forms including bacteria, yeast, rodents, and mammals. Three rare human genetic diseases have defects in the DNA repair system called nucleotide excision repair (NER). Patients with xeroderma pigmentosum (XP) have defective NER and a more than 10,000-fold increased frequency of skin cancer, whereas patients with Cockayne syndrome (CS) or with trichothiodystrophy (TTD) have NER defects without increase in cancer. These are strikingly different clinical phenotypes (Figure 1). The dramatic differences in their manifestations reflect the complexity of DNA repair and the broad scope and central role of DNA repair on preservation of diverse biological functions. This article will review the major milestones in our understanding of DNA repair and skin cancer (Table 1). These include recognition of the clinical diseases, understanding the types of damage sunlight causes in the DNA, recognition of DNA repair in different organisms, discovery of defective DNA repair in humans, cloning of multiple human DNA repair genes, and identification of UV-type mutations in skin cancer.Table 1Timeline for milestones of DNA repair and skin cancer researchDatesMilestoneClinical descriptions of diseases:1874Xeroderma pigmentosum (XP)1936Cockayne syndrome (CS)1971Trichothiodystrophy (TTD)1950-1969Identification of UV-induced DNA photoproducts: cyclobutane pyrimidine dimers (CPD), 6-4 pyrimidine-pyrimidone photoproducts (6-4PP)1960sRecognition of DNA repair in bacteria, repair replication1968Reduced nucleotide excision repair (NER) in XP1960-1979Defective DNA repair in humans: XP and CS complementation groups1971-1975Description of XP variant: normal NER with defective postreplication repair1974Description of XP/CS complex1985Identification of transcription coupled repair (TCR): removal of UV-induced CPD from active genes is more efficient than from the genome overall1980-1999Cloning of human NER repair genes1993Dual role of XPB and XPD helicases in NER and in transcription as part of basal transcription factor IIH (TFIIH)1928UV induction of skin cancer in mouse models1941Quantitation of UV induction of skin cancer in mice1977UV-treated thyroid cells produce tumors in fish, reduced by photoreactivation1991UV-type mutations in p53 tumor suppressor gene in squamous cell carcinomas of human skin1994Sunburn cells are apoptotic keratinocytes with inactivating mutations in p53. Sunlight-inducted mutations in p53 in skin act as both a tumor initiator and a tumor promoter Open table in a new tab Moriz Kaposi made many important contributions to dermatology in the late nineteenth century. He moved from Hungary to Vienna, changed his name from Moriz Kohn, married the daughter of Professor Ferdinand Hebra, and co-authored a famous text with him (Hebra and Kaposi, 1874Hebra F. Kaposi M. On diseases of the skin including exanthemata.The New Sydenham Society LXI. 1874; III: 252-258Google Scholar). In this early textbook of dermatology, he presented an 18-year-old girl with ''xeroderma or parchment skin'' (Hebra and Kaposi, 1874Hebra F. Kaposi M. On diseases of the skin including exanthemata.The New Sydenham Society LXI. 1874; III: 252-258Google Scholar). There was an exquisitely detailed description of the pigmentary changes of her skin with abrupt cutoff at sun-shielded sites. She also had eye involvement. The skin was described as ''parchment like and wrinkled.'' This patient died of ''cancer of the peritoneum.'' A second patient was a 10-year-old girl who developed a large ''epithelioma'' of her nose in addition to lesions on her cheek and upper lip that were ''fissured tubercle of the size of a pea,'' thus suggesting the presence of skin cancers. XP with neurological abnormalities was described in 1883 by Albert Neisser from Germany (who also discovered the bacteria that causes gonorrhea, Neisseria; Neisser et al., 1883Neisser A. Ueber das 'Xeroderma pigmentosum' (Kaposi): Lioderma essentialis cum melanosi et telangiectasia.Vierteljahrschr Dermatol Syphil. 1883; : 47-62Crossref Scopus (18) Google Scholar) and then again in 1932 by the Italians, Carlo deSanctis and Aldo Cacchione (deSanctis-Cacchione syndrome; de Sanctis and Cacchione, 1932de Sanctis C. Cacchione A. L'idiozia xerodermica.Riv Sper Freniatr Med Leg Alien Ment. 1932; 56: 269-292Google Scholar). The well-studied groups of XP patients were reported from the US National Institutes of Health (NIH) in 1974 (15 patients) (Robbins et al., 1974Robbins J.H. Kraemer K.H. Lutzner M.A. et al.Xeroderma pigmentosum. An inherited diseases with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair.Ann Intern Med. 1974; 80: 221-248Crossref PubMed Scopus (604) Google Scholar) (Figure 1a-c) and in 2011 (106 patients) (Bradford et al., 2011Bradford P.T. Goldstein A.M. Tamura D. et al.Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair.J Med Genet. 2011; 48: 168-176Crossref PubMed Scopus (313) Google Scholar), and from Japan in 1977 (50 patients) (Takebe et al., 1977Takebe H. Miki Y. Kozuka T. et al.DNA repair characteristics and skin cancers of xero-derma pigmentosum patients in Japan.Cancer Res. 1977; 37: 490-495PubMed Google Scholar) and in 1994 (29 patients) (Nishigori et al., 1994Nishigori C. Moriwaki S. Takebe H. et al.Gene alterations and clinical characteristics of xeroderma pigmentosum group A patients in Japan.Arch Dermatol. 1994; 130: 191-197Crossref PubMed Scopus (79) Google Scholar). An extensive literature review in 1987 described clinical features of 830 XP patients (Kraemer et al., 1987Kraemer K.H. Lee M.M. Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases.Arch Dermatol. 1987; 123: 241-250Crossref PubMed Scopus (964) Google Scholar). XP patients under 20 years of age were found to have a more than 10,000-fold increased risk of development of skin cancer (basal cell carcinoma, squamous cell carcinoma, or melanoma) (Kraemer et al., 1994Kraemer K.H. Lee M.M. Andrews A.D. et al.The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm.Arch Dermatol. 1994; 130: 1018-1021Crossref PubMed Scopus (481) Google Scholar;Bradford et al., 2011Bradford P.T. Goldstein A.M. Tamura D. et al.Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair.J Med Genet. 2011; 48: 168-176Crossref PubMed Scopus (313) Google Scholar). Edward Alfred Cockayne, in England, reported two siblings (7-year-old girl and 6-year-old boy) having dwarfism with retinal atrophy and deafness. Their faces were described as ''small with sunken eyes... with short, slender trunks and unduly long legs, and their feet and hands are too large in proportion.'' They ''appear to be a little below the average in intelligence and are far more excitable and laugh much more readily than children of normal mentality...'' (Cockayne et al., 1936Cockayne E.A. Dwarfism withretinal atrophy and deafness.Arch Dis Child. 1936; 11: 1-8Crossref PubMed Scopus (223) Google Scholar). A follow-up in 1946 reported that the children had ''deeply sunk eyes and partial absorption of the orbital fat.'' Cataracts had been removed and there was sunburning and marked weight loss (Cockayne et al., 1946Cockayne E.A. Dwarfism with retinal atrophy and deafness.Arch Dis Child. 1946; 21: 52-54Crossref Scopus (94) Google Scholar). In 1992, Martha Nance and Susan Berry in the United States (Nance and Berry, 1992Nance M.A. Berry S.A. Cockayne syndrome: review of 140 cases.Am J Med Genet. 1992; 42: 68-84Crossref PubMed Scopus (628) Google Scholar) published a comprehensive literature review of 140 CS patients. These patients frequently had poor growth and neurologic abnormality, sensorineural hearing loss, cataracts, pigmentary retinopathy, photosensitivity, and dental caries (Figure 1d). The mean age at death was 12.5 years. There were no reports of cancer. TTD was initially described by Chong Hai Tay (Tay et al., 1971Tay C.H. Ichthyosiform erythroderma, hair shaft abnormalities, and mental and growth retardation. A new recessive disorder.Arch Dermatol. 1971; 104: 4-13Crossref PubMed Scopus (78) Google Scholar) as ''ichthyosiform erythroderma, hair shaft abnormalities, mental and growth retardation,'' a new recessive disorder, in three children in a Chinese family in Singapore. The hair shafts were easily broken and showed pili torti and trichorrhexis nodosa-like defects and polarized microscopy revealed an alternating pattern of light and dark transverse bands. This ''tiger tail banding'' along with low sulfur content was also described in the United States by Howard Baden (Baden et al., 1976Baden H.P. Jackson C.E. Weiss L. et al.The physicochemical properties of hair in the BIDS syndrome.Am J Hum Genet. 1976; 28: 514-521PubMed Google Scholar), and by Vera Price (Price et al., 1980Price V.H. Odom R.B. Ward W.H. et al.Trichothiodystrophy: sulfur-deficient brittle hair as a marker for a neuroectodermal symptom complex.Arch Dermatol. 1980; 116: 1375-1384Crossref PubMed Scopus (189) Google Scholar) who gave the disorder the name trichothiodystrophy (sulfur-deficient brittle hair). A comprehensive review of the literature from the NIH reported on 112 published TTD cases (Faghri et al., 2007Faghri S. DiGiovanna J.J. Tamura D. et al.Trichothiodystrophy includes a broad spectrum of multisystem abnormalities and may have a high mortality at a young age.J Invest Dermatol. 2007; 127: 106PubMed Google Scholar). TTD patients commonly had developmental delay/intellectual impairment, short stature, ichthyosis, abnormal birth characteristics, ocular abnormalities including juvenile cataracts, infections, and photosensitivity (Figure 1e and f). Surprisingly, there was a high frequency of maternal pregnancy complications. TTD patients had a high mortality with a 20-fold increased risk of death under the age of 10 years. There were no reports of cancer in classical TTD patients; how-ever, patients who have both TTD and XP (the XP/TTD complex) had increased risk of skin cancer (Broughton et al., 2001Broughton B.C. Berneburg M. Fawcett H. et al.Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene.Hum Mol Genet. 2001; 10: 2539-25347Crossref PubMed Scopus (89) Google Scholar). In 1953, James Watson and Frances Crick in England published the helical structure of nucleic acids in DNA (Watson and Crick, 1953Watson J.D. Crick F.H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid.Nature. 1953; 171: 737-738Crossref PubMed Scopus (8368) Google Scholar). After 7 years, Rob Buekers and W Berands in the Netherlands (Beukers and Berends, 1960Beukers R. Berends W. Isolation and identification of the irradiation product of thymine.Biochim Biophys Acta. 1960; 41: 550-551Crossref PubMed Scopus (233) Google Scholar) reported that UV irradiation (254 nm) of a frozen solution of thymine in water produced an irradiation product: the thymine dimer with the dimers joined covalently with a cyclobutane bond—the cyclobutane pyrimidine dimer (CPD) (50 years later, the theories and experiments that were used to make this seminal discovery were recollected by one of these scientists (Beukers et al., 2008Beukers R. Eker A.P. Lohman P.H. 50 years thymine dimer.DNA Repair (Amst). 2008; 7: 530-543Crossref PubMed Scopus (78) Google Scholar)). These UV-induced photoproducts could be repaired. Although photoreactivation, which directly reverses the CPD in DNA in the presence of long wavelength (UVA or visible) light, was known since the 1940s (Dulbecco et al., 1949Dulbecco R. Reactivation of ultra-violet-inactivated bacteriophage by visible light.Nature. 1949; : 163-949Google Scholar;Kelner et al., 1949Kelner A. Effect of visible light on the recovery of Streptomyces Griseus Conidia from ultra-violet irradiation injury.Proc Natl Acad Sci USA. 1949; 35: 73-79Crossref PubMed Scopus (149) Google Scholar), other scientists in the United States found that yeast contained photoreactivating enzyme (Wulff and Rupert, 1962Wulff D.L. Rupert C.S. Disappearance of thymine photodimer in ultraviolet irradiated DNA upon treatment with a photoreactivating enzyme from baker's yeast.Biochem Biophys Res Commun. 1962; 7: 237-240Crossref PubMed Scopus (74) Google Scholar);Cook et al., 1967Cook J.S. Direct demonstration of the monomerization of thymine-containing dimers in U.V.-irradiated DNA by yeast photoreactivating enzyme and light.Photochem Photobiol. 1967; 6: 97-101Crossref PubMed Scopus (32) Google Scholar). Reginald Deering and Richard Setlow in the United States (Deering and Setlow, 1963Deering R.A. Setlow R.B. Effects of ultraviolet light on thymidine dinucleotide and polynucleotide.Biochim Biophys Acta. 1963; 68: 526-534Crossref PubMed Scopus (7) Google Scholar, Setlow and Carrier, 1964Setlow R.B. Carrier W.L. The disappearance of thymine dimers from DNA: An error-corecting mechanism.Proc Natl Acad Sci USA. 1964; 51: 226-231Crossref PubMed Scopus (507) Google Scholar) reported that with longer wavelength, UV (280 nm) thymine dimers were formed, whereas with shorter wavelengths (239 nm) the reaction could be reversed (photo-reversal). Using this information the husband and wife team of Richard and Jane Setlow performed a series of elegant experiments that showed a biological effect of thymine dimers (Setlow and Setlow and Setlow, 1962Setlow R.B. Setlow J.K. Evidence that ultraviolet-induced thymine dimers in DNA cause biological damage.Proc Natl Acad Sci USA. 1962; 48: 1250-1257Crossref PubMed Scopus (129) Google Scholar). They demonstrated inactivation of transforming activity of DNA in bacteria and phage by 280nm UV treatment and its reactivation by treatment with 239nm UV. In 1963, Setlow et al. demonstrated that one thymine dimer was sufficient to inactivate replicating DNA in bacteria (Setlow et al., 1963Setlow R.B. Swenson P.A. Carrier W.L. Thymine dimers and inhibition of DNA synthesis by ultraviolet irradiation of cells.Science. 1963; 142: 1464-1466Crossref PubMed Scopus (182) Google Scholar). Importantly, this same study reported that there were resistant strains that were able to overcome the block. This was an early suggestion that repair of DNA damage might occur (Setlow described this early research in a 2000 lecture in the NIH DNA Repair Interest Group video conference series "Reflections on how I was led into and onto DNA repair'' http://videocast.nih.gov/launch.asp?10600). The DNA photoproducts were found to involve pyrimidines and not purines. CPD were found with T = T and T = C. A third thymine containing photoproduct was later reported by the US scientists, Varghese and colleagues— the thymine-cytosine 6-4 photoproduct (6-4PP) (Varghese and Wang, 1967Varghese A.J. Wang S.Y. Ultraviolet irradia-tion of DNA in vitro and in vivo produces a 3d thymine-derived product.Science. 1967; 156: 955-957Crossref PubMed Scopus (73) Google Scholar, Wang et al., 2010Wang Y. Tan X.H. DiGiovanna J.J. et al.Genetic diversity in melanoma metastases from a patient with xeroderma pigmentosum.J Invest Dermatol. 2010; 130: 1188-1191Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar; Varghese and Patrick, 1969Varghese A.J. Patrick M.H. Cytosine derived heteroadduct formation in ultraviolet-irradiated DNA.Nature. 1969; 223: 299-300Crossref PubMed Scopus (33) Google Scholar). In 1964 in the United States, Richard Boyce and Paul Howard-Flanders (Boyce and Howard-Flanders, 1964Boyce R.P. Howard-Flanders P. Release of ultraviolet light-induced thymine dimers from DNA in E. coli K-12.Proc Natl Acad Sci USA. 1964; 51: 293-300Crossref PubMed Scopus (374) Google Scholar) and Setlow and William Carrier (Setlow and Carrier, 1964Setlow R.B. Carrier W.L. The disappearance of thymine dimers from DNA: An error-corecting mechanism.Proc Natl Acad Sci USA. 1964; 51: 226-231Crossref PubMed Scopus (507) Google Scholar) independently reported that UV-resistant strains of E. coli remove thymine dimers from their DNA whereas sensitive strains do not. These papers suggested that a DNA repair process was involved in recovery from UV treatment. This process was called ''dark repair'' as removal occurred without additional light exposure, in contrast to photoreversal that required 240nm UV and to enzymatic photoreactivation by photoreactivating enzyme that required long wavelength or visible light. Phillip Hanawalt, after receiving his degree as the first graduate student of Richard Setlow at Yale University (Setlow et al., 2005Setlow R.B. My early days in photobiology with Philip Hanawalt.Mutat Res. 2005; 577: 4-8Crossref PubMed Scopus (4) Google Scholar), took a postdoctoral fellowship in Denmark. There, he learned about BrdU—a nucleic acid analog of higher density than thymine. After returning to the United States, at Stanford University, Hanawalt used BrdU to analyze the location of newly synthesized DNA in bacteria following removal of thymine dimers. In cesium chloride density gradients, newly synthesized DNA containing BrdU would migrate at a different density than the parental DNA containing thymine. They performed BrdU pulse labeling experiments on UV-treated bacterial cells. A statement in the classic 1964 paper contains the basis of our current knowledge of DNA repair: ''Our findings are consistent with the view that in ultraviolet-resistant organisms a mechanism for repair replication exists in which damaged single-strand regions of the chromosome can be excised and replaced, using the undamaged DNA strand as template'' (Pettijohn and Hanawalt, 1964Pettijohn D. Hanawalt P. Evidence for repair-replication of ultraviolet damaged DNA in bacteria.J Mol Biol. 1964; 9: 395-410Crossref PubMed Scopus (258) Google Scholar) (see also the 2002 video of Hanawalt's description of early DNA repair studies ''Half a Century of DNA Repair: an Historical Perspective;http://videocast.nih.gov/launch.asp?10587). The search for the enzymes that carried out DNA repair yielded interesting results. Setlow reported an endonuclease in T4 phage that cut DNA at cyclobutane dimers (Setlow et al., 1970Setlow R.B. Setlow J.K. Carrier W.L. Endonuclease from Micrococcus luteus which has activity toward ultraviolet-irradiated deoxy-ribonucleic acid: its action on transforming deoxyribonucleic acid.J Bacteriol. 1970; 102: 187-192PubMed Google Scholar). Intensive research by many labs found that removal of UV photoproducts in bacteria was primarily accomplished by the multiprotein UvrABC system (reviewed by a pioneer scientist, Larry Grossman in the United states (Grossman et al., 1988Grossman L. Caron P.R. Mazur S.J. et al.Repair of DNA-containing pyrimidine dimers.FASEBJ. 1988; 2: 2696-2701PubMed Google Scholar) (see the 1999 video of Grossman ''Four decades of DNA repair: from populations of molecules to populations of peopl e'' http://videocast.nih.gov/launch. asp?10595). However, this is a different DNA repair system from that in higher organisms. In 1964, Donald Rasmussen and Robert Painter in the United States reported evidence of repair replication in mammalian cells by finding increased incorporation of radioactive thymidine following UV exposure to cultured hamster and human (HeLa) cells (Rasmussen and Painter, 1964Rasmussen R.E. Painter R.B. Evidence for repair of ultraviolet damaged DNA in cultured mammalian cells.Nature. 1964; 203: 1360-1362Crossref PubMed Scopus (181) Google Scholar). By use of autoradiography, they also showed that, unlike the scheduled S-phase DNA synthesis, this post-UV thymine incorporation occurs in nearly all cells in all phases of the cell cycle and thus is ''unscheduled DNA synthesis'' (UDS). James Cleaver, working as a postdoc in the Painter laboratory, read a newspaper article about patients with sun sensitive disorder, XP, who had increased skin cancer risk. In 1968, he reported that cultured skin cells from XP patients had reduced post-UV repair replication (measured by use of H3- BrdU in cesium chloride gradients) and reduced UDS (measured by autoradiography) compared cells from normal donors (Cleaver et al., 1968Cleaver J.E. Defective repair replication of DNA in xeroderma pigmentosum.Nature. 1968; 218: 652-656Crossref PubMed Scopus (1274) Google Scholar). This seminal result thus linked defective DNA repair to increased cancer risk (see 2001 video of Cleaver ''Mending human genes'' http://videocast.nih.gov/launch.asp?10561). Setlow et al. wrote in 1969 that they based their work on previous studies in bacteria that found that the mechanism of excision of UV induced dimers is a multistep process involving ''(1) a single-strand break on one side of a dimer;(2) dimer excision as a result of a second break on the same strand; (3) repair replication which fills in the resulting gap;and (4) closure of the gap by ligase action'' (Setlow et al., 1969Setlow R.B. Regan J.D. German J. et al.Evidence that xeroderma pigmentosum cells do not perform the first step in the repair of ultraviolet damage to their DNA.Proc Natl Acad Sci USA. 1969; 64: 1035-1041Crossref PubMed Scopus (375) Google Scholar). In an analogous manner, they reported that cultured skin cells from an XP patient did not remove UV-induced thymine dimers from their DNA and did not perform the first step involving DNA strand breaks required for excising dimers. This finding pointed to dimers as playing an important role in UV-induced skin cancer in humans. In Rotterdam, The Netherlands, the group led by Dirk Bootsma fused cultured fibroblasts from XP patients with neurological abnormalities with cultured fibroblasts from XP patients without these abnormalities. They then performed post-UV UDS assay with autoradiography. They found that certain combinations of cells had increased UDS, indicating that each cell provided what the other was lacking—they complemented the repair defect (De Weerd-Kastelein et al., 1972De Weerd-Kastelein E.A. Keijzer W. Bootsma D. Genetic heterogeneity of xeroderma pigmentosum demonstrated by somatic cell hybridization.Nat New Biol. 1972; 238: 80-83Crossref PubMed Scopus (238) Google Scholar). This implied that each complementation group had a different genetic defect. In the United States, Jay Robbins began studying patients with XP at the NIH by examining patients with different clinical features (Robbins et al., 1974Robbins J.H. Kraemer K.H. Lutzner M.A. et al.Xeroderma pigmentosum. An inherited diseases with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair.Ann Intern Med. 1974; 80: 221-248Crossref PubMed Scopus (604) Google Scholar) (Figure 1a-c). There were eight XP patients with abnormalities confined to their skin and eyes. Five XP patients, in addition, had progressive neurological degeneration. One XP patient had skin and eye abnormalities plus neurological degeneration with extremely short stature and immature sexual development—features of a second disorder, CS—the first patient described with the XP/CS complex (Figure 1c). All 14 of these XP patients had reduced UDS. Cell fusion studies revealed that they represented four XP complementation groups (Kraemer et al., 1975aKraemer K.H. Coon H.G. Petinga R.A. et al.Genetic heterogeneity in xeroderma pigmentosum: complementation groups and their relationship to DNA repair rates.Proc Natl Acad Sci USA. 1975; 72: 59-63Crossref PubMed Scopus (118) Google Scholar). As the cells assigned to each complementation group had a similar range rate of residual DNA repair, the XP complementation groups were named in order of increasing residual repair (XP-A to XP-D) (Kraemer et al., 1975aKraemer K.H. Coon H.G. Petinga R.A. et al.Genetic heterogeneity in xeroderma pigmentosum: complementation groups and their relationship to DNA repair rates.Proc Natl Acad Sci USA. 1975; 72: 59-63Crossref PubMed Scopus (118) Google Scholar). An arrangement between the NIH scientists and the group in Rotterdam set the model for collaboration in the early stages of these investigations that has followed to the present day. These groups exchanged cell lines and determined that there were five XP DNA repair complementation groups (XP-A to XP-E) (Kraemer et al., 1975bKraemer K.H. De Weerd- Kastelein E.A. Robbins J.H. et al.Five complementation groups in xeroderma pigmentosum.Mutat Res. 1975; 33: 327-340Crossref PubMed Scopus (152) Google Scholar). In 1979, a Japanese group reported a patient with low UDS and mild disease, forming complementation group XP-F (Arase et al., 1979Arase S. Kozuka T. Tanaka K. et al.A sixth complementation group in xeroderma pigmentosum.Mutat Res. 1979; 59: 143-146Crossref PubMed Scopus (96) Google Scholar). A Dutch group reported another patient with low UDS and no skin cancers forming complementation group XP-G (Keijzer et al., 1979Keijzer W. Jaspers N.G. Abrahams P.J. et al.A seventh complementation group in excision-deficient xeroderma pigmentosum.Mutat Res. 1979; 62: 183-190Crossref PubMed Scopus (139) Google Scholar) (see also the 2010 video of Kenneth Kraemer and Vilhelm Bohr ''History of DNA repair: Four decades of DNA repair at NIH and the first twenty-five years of the DNA Repair Interest Group'' http://videocast.nih.gov/launch.asp?15954). One of the NIH patients (XP4BE) had severe disease but normal UDS in skin and blood cells (Burk et al., 1971aBurk P.G. Lutzner M.A. Clarke D.D. et al.a Ultraviolet-stimulated thymidine incorporation in xeroderma pigmentosum lymphocytes.J Lab Clin Med. 1971; 77: 759-767PubMed Google Scholar, Burk et al., 1971bBurk P.G. Yuspa S.H. Lutzner M.A. et al.Xeroderma pigmentosum and D. N. A. repair.Lancet. 1971; 1: 601Abstract PubMed Scopus (26) Google Scholar; Robbins and Burk, 1973Robbins J.H. Burk P.G. Relationship of DNA repair to carcinogenesis in xeroderma pigmentosum.Cancer Res. 1973; 33: 929-935PubMed Google Scholar;Robbins et al., 1974Robbins J.H. Kraemer K.H. Lutzner M.A. et al.Xeroderma pigmentosum. An inherited diseases with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair.Ann Intern Med. 1974; 80: 221-248Crossref PubMed Scopus (604) Google Scholar) (Figure 1b). These patients have been called XP variants (Cleaver et al., 1972Cleaver J.E. Xeroderma pigmentosum: variants with normal DNA repair and normal sensitivity to ultraviolet light.J Invest Dermatol. 1972; 58: 124-128Abstract Full Text PDF PubMed Scopus (174) Google Scholar). In 1975, Alan Lehmann and colleagues in the United Kingdom reported that XP variant cells had normal NER but defective post-replication repair, a process of DNA synthesis after UV irradiation (Lehmann et al., 1975Lehmann A.R. Kirk-Bell S. Arlett C.F. et al.Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation.Proc Natl Acad Sci USA. 1975; 72: 219-223Crossref PubMed Scopus (525) Google Scholar). They also showed that, unlike normal cells, this process was inhibited by caffeine. see also the 2013 video of Lehmann ''Human DNA Repair Disorders: A Historical Perspective 1968-2013'' http://videocast.nih.gov/launch.asp?17965. One of the NIH patients (XP4BE) had severe disease but normal UDS in skin and blood cells (Burk et al., 1971aBurk P.G. Lutzner M.A. Clarke D.D. et al.a Ultraviolet-stimulated thymidine incorporation in xeroderma pigmentosum lymphocytes.J Lab Clin Med. 1971; 77: 759-767PubMed Google Scholar, Burk et al., 1971bBurk P.G. Yuspa S.H. Lutzner M.A. et al.Xeroderma pigmentosum and D. N. A. repair.Lancet. 1971; 1: 601Abstract PubMed Scopus (26) Google Scholar; Robbins and Burk, 1973Robbins J.H. Burk P.G. Relationship of DNA repair to carcinogenesis in xeroderma pigmentosum.Cancer Res. 1973; 33: 929-935PubMed Google Scholar;Robbins et al., 1974Robbins J.H. Kraemer K.H. Lutzner M.A. et al.Xeroderma pigmentosum. An inherited diseases with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair.Ann Intern Med. 1974; 80: 221-248Crossref PubMed Scopus (604) Google Scholar) (Figure 1b). These patients have been called XP variants (Cleaver et al., 1972Cleaver J.E. Xeroderma pigmentosum: variants with normal DNA repair and normal sensitivity to ultraviolet light.J Invest Dermatol. 1972; 58: 124-128Abstract Full Text PDF PubMed Scopus (174) Google Scholar). In 1975, Alan Lehmann and colleagues in the United Kingdom reported that XP variant cells had normal NER but defective post-replication repair, a process of DNA synthesis after UV irradiation (Lehmann et al., 1975Lehmann A.R. Kirk-Bell S. Arlett C.F. et al.Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation.Proc Natl Acad Sci USA. 1975; 72: 219-223Crossref PubMed Scopus (525) Google Scholar). They also showed that, unlike normal cells, this process was inhibited by caffeine. see also the 2013 video of Lehmann ''Human DNA Repair Disorders: A Historical Perspective 1968-2013''http://videocast.nih.gov/launch.asp?17965). In 1977, R Schmickel and colleagues in the United States reported that cultured skin fibroblasts from two patients with CS were hypersensitive to killing by UV but had normal survival after X-ray treatments (Schmickel et al., 1977Schmickel R.D. Chu E.H. Trosko J.E. et al.Cockayne syndrome: a cellular sensitivity to ultraviolet light.Pediatrics. 1977; 60: 135-139PubMed Google Scholar). CS cells had normal rate of removal of thymine dimers (Schmickel et al., 1977Schmickel R.D. Chu E.H. Trosko J.E. et al.Cockayne syndrome: a cellular sensitivity to ultraviolet light.Pediatrics. 1977; 60: 135-139PubMed Google Scholar) and normal UDS (Andrews et al., 1978Andrews A.D. Barrett S.F. Yoder F.W. et al.Cockayne's syndrom
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