Mechanisms of DNA damage, repair, and mutagenesis

Abstract

Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue. Environ. Mol. Mutagen. 58:235-263, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: base excision repair; mismatch repair; nucleotide excision repair; single and double strand break repair; telomeres; translesion synthesis.

Figure 1

Common DNA base lesions. A) Normal structures of DNA bases: adenine (A), guanine (G), cytosine (C) and thymine (T). B) Deaminated bases: hypoxanthine, xanthine, uracil and thymine arising from deamination of exocyclic bases of adenine, guanine, cytosine and 5-methylcytosine (5-mC) respectively. C) Oxidized DNA bases: formamidopyrimidine derivative of adenine (Fapy-A), 7,8 dihydro-8-oxoguanine (8-oxo-G) and thymine glycol. D) Methylated DNA bases: N3-methyladenine, N7-methylguanine, O⁶-methylguanine, N3-methylcytosine, O⁴-methylthymine, O⁴-ethylthymine and N3-methylthymine.

Figure 2

Main UV radiation-induced DNA base lesions. A) Representative cyclobutane pyrimidine dimers (CPD). Shown here are cyclobutane thymine dimers. B) Representative pyrimidine (6 – 4) pyrimidone photoproduct [(6 – 4)PP]. Shown here are derivatives of two thymine bases linked via C6 of one thymine base and C4 of the other thymine base.

Figure 3

Structures of representative DNA damaging agents. A) Alkylating agents: methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), N-methyl -N′ –nitro-N-nitrosoguanidine (MNNG) and methylnitrosourea (MNU). B) Crosslinking agents: Cyclophosphamide, cisplatin and psoralen. C) Aromatic amines: 2-aminofluorene (AF) and N-acetyl-2-aminofluorene (AAF). D) Polycyclic aromatic hydrocarbons: benzo(a)pyrene and dibenzo[a,l]pyrene. E) Reactive electrophiles: 4-nitroquinoline 1-oxide (4-NQO). F) Toxins: Afaltoxin B1.

Figure 4

Schematic of various DNA damage-induced DNA repair pathways. A variety of DNA damaging agents can induce DNA damage, which becomes substrate for specific DNA repair pathways. Upper panel shows representative DNA damaging agents: errors from replication, spontaneous base deamination, alkylating agents, toxins, oxidative agents, ionizing radiation, UV radiation, crosslinking agents, aromatic compounds and environmental agents such as heat, cold and hypoxia. Middle panel represents different kinds of damaged DNA: base mismatches (C:T), uracil from deamination of cytosine, an abasic site from the loss of a base from one DNA strand, methylated guanine, methylated adenine, 8-oxo-G lesion, thymine glycols, single strand breaks, double strand breaks, intrastrand cyclobutane thymine dimers and interstrand guanine crosslinks. The lower panel lists the specific DNA repair pathways that are instigated to repair DNA damages: mismatch repair corrects replication errors and other base mismatches; base excision repair removes base adducts, uracil, abasic sites and oxidative lesions; single strand break repair pathways repairs single stranded breaks in the DNA backbone; double strand break repair pathway repair double strand breaks; nucleotide excision repair removes bulky lesions and intrastrand crosslinks; interstrand crosslink repair removes interstrand linkages and translesion synthesis bypasses intrastrand crosslinks and bulky lesions.