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Home Books Fitzpatrick's Dermatology in General Medicine, 8e

Chapter 110. Genome Instability, DNA Repair, and Cancer

Thomas M. Rünger; Kenneth H. Kraemer

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Genome Instability, DNA Repair, and Cancer at a Glance
  • DNA can be damaged by physical agents (ultraviolet or ionizing radiation) or chemical agents in the environment.
  • DNA damage may lead to mutations (changes in DNA sequence).
  • The ability of cells to repair DNA damage and to maintain genome stability is of utmost importance to prevent malignant transformation.
  • Different agents induce different types of DNA damage, which in turn require different responses and repair pathways.
  • A number of hereditary disorders are characterized by genome instability due to defects in genes involved in DNA repair or DNA damage signaling.
  • Many different laboratory tests can be used to diagnose genome instability and/or DNA repair defects.
  • Inherited or acquired genome instability is associated with an increased cancer risk.

The integrity of the genome of all living organisms is constantly threatened by exogenous and endogenous DNA-damaging agents. Exogenous DNA-damaging agents include physical agents, such as ultraviolet (UV) or ionizing radiation (IR), and a wide variety of chemical agents, such as components of cigarette smoke. Endogenous DNA damage arises from regular metabolic processes within the cell, mediated, for example, by reactive oxygen species. Maintaining the stability of the genome is of utmost importance to all living organisms. Therefore, since early evolution, all organisms ranging from prokaryotes to eukaryotes have been equipped with mechanisms that react to and repair DNA damage and thereby maintain genomic stability. The types of damage produced include alterations in the structure of nucleotides, DNA strand breaks, DNA cross-links, and DNA adducts. Different types of DNA-damaging agents induce different types of DNA damage (Table 110-1), which in turn require different responses and repair pathways for processing (Table 110-2).1

Table 110-1 Cellular Damage Induced by Physical and Chemical Agents
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Table 110-1 Cellular Damage Induced by Physical and Chemical Agents

Agent

Damage

Ultraviolet (UV) radiation

Dipyrimidine cyclobutane dimers (TT, TC, CT, or CC), pyrimidine-pyrimidone (6–4) photoproducts (mostly TC), DNA-protein cross-links

X-irradiation

DNA single- and double-strand breaks, oxidative base damage

Psoralens plus UVA

DNA-psoralen monoadducts, DNA interstrand cross-links (binds to T at TA sequences)

Mitomycin C

DNA interstrand cross-links

Benzo-[a]-pyrene

Bulky adducts

Reactive oxygen species

Oxidative base damage (8-oxo-deoxyguanine, thymine glycol), cyclopurines (A or G) making bulky lesions

Table 110-2 Types of DNA Damage and Associated DNA Repair Pathways
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Table 110-2 Types of DNA Damage and Associated DNA Repair Pathways

Type of DNA Damage

DNA Repair Pathway

DNA photoproducts (CPDs, 6,4-PP)

Nucleotide excision repair (NER)

Oxidative base modifications (e.g., 8-oxoG)

Base excision repair

Incorrect DNA base pairing

Mismatch repair

DNA double-strand breaks

Nonhomologous end joining, homologous recombination (i.e., recombination repair)

DNA adducts

NER

DNA cross-links (interstrand and intrastrand)

Recombination repair

Persistent DNA lesions

Translesion (bypass) DNA synthesis

CPDs = cyclobutane pyrimidine dimers; 6, 4-PP = 6, 4-pyrimidine–pyrimidone photoproducts; 8-oxoG = 8-oxo-deoxyguanine.

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