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DNA Repair Mechanisms and Initiation in Carcinogenesis

Authors
  • Averbeck, D.
Type
Book
Journal
Comprehensive Toxicology
Publication Date
Jan 01, 2010
Pages
49–62
Identifiers
DOI: 10.1016/B978-0-08-046884-6.01404-4
ISBN: 978-0-08-046884-6
Source
Elsevier
Keywords
License
Unknown

Abstract

Cells are permanently exposed to genotoxic insults from internal metabolism and from exposures to chemicals and environmental agents giving rise to lesions in deoxyribonucleic acid (DNA). If not repaired, these may lead to cell death or to mutations, chromosomal aberrations, and initiation of carcinogenesis. During evolution, efficient multienzymatic repair pathways have been developed capable to remove damage before DNA replication or cell proliferation. Repair depends on damage recognition and activation of DNA damage signaling. Genetically controlled DNA repair pathways cope with different types of lesions, that is, mismatch repair (MMR) with replication errors, O 6-guanine methyltransferase or DNA ligase I with simple methylated bases or single-strand breaks (SSBs) arising from alkylations and/or cellular metabolism, base excision repair (BER) with single base damages and complex SSBs induced by oxidants, oxidative chemical radicals, photodynamic sensitizers or ionizing radiation and nucleotide excision repair (NER) with bulky, DNA distorting lesions arising from chemical addition, metabolically activated polyaromatic hydrocarbons (PAHs), photoaddition of photoreactive molecules, or ultraviolet (UV) light-induced photolesions (pyrimidine dimers, 6-4 photoproducts). Complex lesions, that is, DNA double-strand breaks (DSBs) and DNA interstrand cross-links, rely on homologous recombination (HR) or nonhomologous end-joining (NHEJ) repair or sequential processing. Identification of rare human syndromes such as xeroderma pigmentosum (XP), Ataxia-telangiectasia (A-T), Bloom syndrome (BS), and along with knockout animal models have demonstrated a direct link between DNA repair deficiency and predisposition for spontaneous and induced cancers. Also, genetic polymorphisms of DNA repair and other genes can influence cancer predisposition in the general population. Thus, DNA repair activities are imbedded in a network of highly dose-dependent cellular responses involving activation or repression of general cellular metabolism, intra- and intercellular signaling, and epigenetic control. The initial level of DNA damage induced and the individual DNA repair capacity, physiological state, and cellular environment determine the final outcome in terms of carcinogenesis.

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