DNA Damage Types and Sources

DNA damage is any change to the chemical structure of DNA that departs from its normal, undamaged state. It arises both from agents inside the cell, such as reactive oxygen species and the inherent instability of the DNA molecule, and from agents outside it, such as ultraviolet light, ionising radiation, and chemical mutagens. Classifying lesions by their chemistry and source explains why cells need several distinct repair pathways.

Definition

DNA damage refers to chemical or structural alterations of DNA, including modified or missing bases, abasic sites, single- and double-strand breaks, and inter- or intrastrand crosslinks, generated by endogenous processes or by exogenous physical and chemical agents.

Scope

This entry surveys the main categories of DNA lesion, from base modifications and abasic sites to single- and double-strand breaks and crosslinks, and the endogenous and exogenous sources that produce them. It treats damage as the input to the repair system; the pathways that remove these lesions are covered in sibling entries.

Core questions

• What chemical types of lesion can DNA sustain?
• Which sources are endogenous and which are exogenous?
• How frequent is spontaneous, intrinsic DNA damage?
• Why does the type of lesion determine which repair pathway is engaged?

Key concepts

• Endogenous damage
• Exogenous damage
• Oxidative base lesions
• Depurination and deamination
• Alkylation
• Pyrimidine dimers
• Single-strand and double-strand breaks
• Interstrand crosslinks

Key theories

Intrinsic chemical instability of DNA

DNA is not chemically inert: spontaneous hydrolysis causes depurination and deamination at appreciable rates, so a substantial fraction of damage arises from the molecule's own instability rather than from external agents, making repair a continuous requirement.

Mechanisms

Endogenous damage includes hydrolytic loss of bases (depurination) and deamination of cytosine to uracil, oxidative lesions such as 8-oxoguanine generated by reactive oxygen species from metabolism, and errors of replication; Lindahl showed that these spontaneous reactions occur frequently enough to threaten genome integrity on their own. Exogenous sources add further lesions: ultraviolet light produces cyclobutane pyrimidine dimers and 6-4 photoproducts that distort the helix, ionising radiation produces strand breaks including double-strand breaks, and chemical agents produce alkylated bases, bulky adducts, and crosslinks. Because these lesions differ in chemistry and in how much they distort the double helix, they are recognised and processed by different repair systems, which is why damage type and source are the organising principle for the rest of the area.

Clinical relevance

The spectrum of DNA damage underlies the mutagenic and carcinogenic effects of agents such as tobacco smoke, ultraviolet exposure, and ionising radiation, and the deliberate induction of damage is the basis of radiotherapy and many chemotherapies; this entry describes those relationships as mechanistic background and not as advice on exposure or treatment for any individual.

History

Early work treated mutation chiefly as a response to external mutagens, but the recognition that DNA decays spontaneously reframed damage as an unavoidable internal process. Lindahl's 1993 synthesis of the rates of hydrolytic and oxidative decay established the scale of endogenous damage, and later integrative reviews placed the full catalogue of lesions and their sources within the genome-maintenance framework.

Key figures

• Tomas Lindahl
• Jan Hoeijmakers
• Stephen Jackson
• Jiri Bartek

Seminal works

• lindahl-1993
• hoeijmakers-2001
• ciccia-elledge-2010

Frequently asked questions

Does most DNA damage come from the environment?

No. A large share of DNA damage is endogenous, arising from the chemical instability of DNA itself and from reactive oxygen species produced by normal metabolism, in addition to exogenous agents such as ultraviolet light and radiation.

Why are double-strand breaks considered especially dangerous?

A double-strand break severs both strands of the helix at once, so there is no intact complementary strand to copy from at that site; if misrepaired it can cause chromosomal rearrangements, which is why specialised pathways handle it.