Effects of Interferon on Mitomycin C-Induced Sister Chromatid Exchanges and on Ultraviolet Induced Unscheduled DNA Synthesis

This article is about the effects of interferon(IFN)on sisterchromatid exchange(SCE)frequencies induced by mitomycin C(MMC)and/or unscheduled DNA synthesis(UDS)induced by ultra-violet light(UV).The result shows that SCE frequencies in peri-pheral lymphocytes from 4 normal individuals and 3 patients withxeroderma pigmentosum(XP)treated with IFN before the additionof MMC were much lower than those of the controls.But after thetreatment of IFN followed by UV irradiation,no difference was fo-und between the UDS levels of the lymphocytes from 2 normal in-dividuals and 2 patients with XP and those from the controls.Thewriters deduce that IFN may have some effect of antimutation     

Central nervous system dysmyelination in PIBI(D)S syndrome: a further case

This is a report of new case of PIBI(D)S, a rare autosomal recessive syndrome characterized by photosensitivity, ichthyosis, brittle sulfur-deficient hair (trichothiodystrophy), impaired intelligence, decreased fertility, and short stature. Bilateral cataract and axial osteosclerosis were also detected. Magnetic resonance imaging (MRI) revealed diffuse central nervous system dysmyelination, a finding also described in the only three other reported cases in which MRI was performed. The paper also considers certain similarities in neurological signs and neuroradiological findings between PIBI(D)S, Cockayne syndrome, and xeroderma pigmentosum — all of which are inherited diseases characterized by photosensitivity and DNA repair defect.     

着色性干皮病及其恶变：附5例报告

本文报告了我院1972～1985年,13年间共收治5例着色性干皮病患者。结合文献提出:1.本病罕见并与遗传有关;2.只要治疗及时,处理得当,预后并非不良;3.从优生学的角度建议:(1)避免近亲结婚,(2)对患本病的后代应进行常染色体的检查,如发现常染色体异常,应注意病变的出现并做好预防及治疗措施。     

Xeroderma pigmentosum exhibiting neurological disorders and systemic lupus erythematosus

A patient is described who has a unique combination of symptoms that correspond with two sun-sensitive conditions: xeroderma pigmentosum (XP) and systemic lupus erythematows (SLE). Both of these conditions have been suggested as being associated with a defect in DNA repair, but this is only clearly established for XP. The patient described is the only known case among U.S. blacks, thus far, although African black cases are known. Her DNA repair levels are 20–30% of normal, within the range found for many XP cell cultures and consistent with her assignment to group C by other investigators. Unusual for group C cases, however, are the neurological disorders, some of which correspond to those found in the de Sanctis Cacchione form of XP, which is commonly assigned to group A. Whether the associated SLE is a consequence of some special aspect of this particular XP condition or whether it is fortuitous cannot be resolved at present.     

Mutation spectrum in UVB-exposed skin epidermis of a mildly-affected Xpg-deficient mouse

A C-terminal 183 amino acid-truncated mutation of the mouse Xpg gene (XpgDeltaex15) gives rise to a partial deficiency in nucleotide excision repair in homozygously affected cells. We studied the effect of this mutation on UVB-induced mutagenesis in mouse skin, using transgenic mice harboring lambda-phage-based bacterial lacZ genes as a mutational reporter. UVB increased the lacZ mutant frequency in the epidermis moderately in the homozygous mutant mice, but significantly higher than in the wild-type or the heterozygous mice, whereas background mutant frequencies were not appreciably different among the three mouse genotypes. Ninety-eight lacZ mutant sequences isolated from the UVB-exposed epidermis of the XpgDeltaex15-homozygous mice were analyzed and compared with mutant sequences from the wild-type mice. The spectra of the mutations in the two mouse genotypes were not significantly different, and they were highly UV-specific. There were frequent C --> T transitions at dipyrimidine sites and several CC --> TT tandem mutations, although the UV-specific mutations occurred more frequently at CpG sites in the mutant mice. The distribution of the mutations observed in the lacZ transgene and the preferred sequence context of the UV-specific C --> T mutations (5'-TC-3' > 5'-CC-3' > 5'-CT-3') in the Xpg-mutant mice were similar to those found in the wild-type mice. Despite these similarities, we detected a previously unrecognized type of the UV-induced mutation only in the Xpg mutant (6/98 in the mutation spectrum of the mutant vs. 0/76 in the wild-type; P = 0.035), which is characterized by multiple base substitutions or frameshifts within a three-nucleotide sequence containing a dipyrimidine. We propose that this putative new class of mutation, which we refer to as a "triplet mutation", is characteristic of UV-induced mutation in an excision-repair-deficient background.     

Identification of a primarily neurological phenotypic expression of xeroderma pigmentosum complementation group A in a Tunisian family

Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. The disease is classified into eight groups. Among them, XP group A (XP‐A) is characterized by the presence of neurological abnormalities in addition to cutaneous symptoms. In the present study, we report a particular family with XP‐A in which some members showed an atypical clinical presentation, i.e. unexplained neurological abnormalities with discrete skin manifestations. Molecular investigation allowed identification of a novel XPA mutation and complete phenotype–genotype correlation for this new phenotypic expression of XP‐A.     

Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase

Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of cancer, including highly prevalent UV-associated skin carcinomas. The mechanism by which caffeine protects against skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activated by DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase 1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in clinical trials. Conversely, inhibition of other DNA damage response pathways, such as ataxia telangiectasia mutated (ATM) and BRCA1, promotes cancer. To determine the effect of replication checkpoint inhibition on carcinogenesis, we generated transgenic mice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc(-/-). Unlike caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained tumor-free for significantly longer (P = 0.003) and had 69% fewer tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replication checkpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies.     

DNA repair as an emerging target for COPD-lung cancer overlap

Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease (COPD). Many of the detrimental effects of cigarette smoke have been attributed to the development of DNA damage, either directly from chemicals contained in cigarette smoke or as a product of cigarette smoke-induced inflammation and oxidative stress. In this review, we discuss the environmental, epidemiological, and physiological links between COPD and lung cancer and the likely role of DNA damage and repair in COPD and lung cancer development. We explore alterations in DNA damage repair by DNA repair proteins and pathways. We discuss emerging data supporting a key role for the DNA repair protein, xeroderma pigmentosum group C (XPC), in cigarette smoke-induced COPD and early lung cancer development. Understanding the interplay between cigarette smoke, DNA damage repair, COPD, and lung cancer may lead to prognostic tools and new, potentially targetable, pathways for lung cancer prevention and treatment.