DNA repair protects against cutaneous and internal neoplasia: evidence from xeroderma pigmentosum

Abstract

Xeroderma pigmentosum (XP), is a rare, autosomal recessive disease with sun sensitivity and multiple neoplasms in association with reduced DNA repair. As a reflection of the clinical consequences of deficient DNA repair, XP serves as a model for determining the effects of proficient DNA repair. To estimate the risk of developing neoplasms in XP, we abstracted reports of 726 XP patients (from 41 countries) published from 1874 to 1982. Despite limitations of a literature survey, the XP patients under age 20 years had an estimated 2000-fold increase in frequency of basal cell and squamous cell carcinoma of the skin, of cutaneous melanoma, of cancer of the anterior eye, and of cancer of the anterior tongue, in comparison to the general population. These sites are all potentially exposed to u.v. radiation, a strong carcinogen which produces DNA damage that is poorly repaired by XP cells. XP patients under age 20 years also had an estimated 12-fold increase in occurrence of neoplasms in sites not exposed to u.v. radiation. Among the XP patients under age 40 years with internal cancer, there was a disproportionate representation of malignant neoplasms of the brain (especially sarcomas), and oral cavity (excluding tongue) compared to US whites under age 40 years. These internal neoplasms may be related to exposure to chemical environmental carcinogens that cause DNA damage which, like u.v.-induced damage, is poorly repaired by XP cells. These reports provide no evidence of an increase in XP of common lethal neoplasms such as lymphomas, or female genital tract or endocrine system cancers. These findings suggest that DNA repair plays a role in protection against u.v.-induced neoplasia and in protection against some internal neoplasms in the general population.

Nucleotide excision repair and B lymphoma: Somatic hypermutation is not the only culprit

“…15 Despite its importance, NER is strongly attenuated in many types of terminally differentiated cells, such as neurons, 16 macrophages 17 and myocytes. 18 In these cells, NER is concentrated inside nuclear transcription factories, thereby ensuring proper repair of active genes, while the rest of the genome is poorly repaired.…”

Human cells bearing homozygous mutations in the DNA mismatch repair genes hMLH1 or hMSH2 are fully proficient in transcription-coupled nucleotide excision repair

“…NER is comprised of two strongly overlapping subpathways that differ only in the initial (lesion-recognition) step: (i) global NER (GNER), a relatively slow process that removes bulky DNA lesions from the genome overall (including from the nontranscribed strands of active genes); and (ii) transcription-coupled NER (TCNER) which brings about more rapid repair of such lesions that are located uniquely on the transcribed strands of active genes (de Laat et al, 1999). Xeroderma pigmentosum (XP) patients, who are universally characterized by deficiency either in GNER alone, or in both GNER and TCNER, display extreme cutaneous photosensitivity that is accompanied by a dramatic (2000-fold) increase in the frequency of sunlight-induced skin cancers (Kraemer et al, 1984). On the other hand, individuals afflicted with Cockayne syndrome (CS) are defective only in TCNER (Venema et al, 1990), and, except for cutaneous photosensitivity, manifest a much different phenotype than XP patients, i.e., growth failure, developmental defects, and no predisposition to skin cancer (Berneburg and Lehmann, 2001;Nance and Berry, 1992).…”

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency

“…The XP-C group of XP patients has mutations in the DNA damage-recognition protein XPC involved in global nucleotide excision repair (GGR). They are characterized by UV hypersensitivity, sun-induced cutaneous features such as hypopigmentation and hyperpigmentation, and a greatly (>1,000-fold) increased incidence of cancer (1)(2)(3). In contrast, CS patients have mutations in the RNA polymerase II cofactors CSA and CSB, which recognize damage in transcribed regions through transcription arrest (transcriptioncoupled repair, TCR).…”