DNA is chemically stable enough to store information for long periods, but it is not inert. DNA lesions arise continually from ordinary chemistry inside cells and from external physical or chemical agents.

A source of DNA damage is called endogenous when it originates within the cell and exogenous when it comes from the environment.

Spontaneous chemical changes

Several reactions can occur without an external mutagen.

• Depurination hydrolyzes the bond connecting a purine base to the sugar, leaving an abasic site with no base attached.
• Deamination removes an amino group from a base. For example, deamination of cytosine can produce uracil, which does not carry the same base-pairing information as cytosine.
• Reactive oxygen-containing molecules generated by ordinary cellular chemistry can oxidize DNA bases and the sugar-phosphate backbone.

These processes make spontaneous DNA damage unavoidable even in a protected environment.

Radiation and chemical agents

External agents can generate characteristic lesions.

Ultraviolet light can promote covalent bonding between neighboring pyrimidine bases in the same DNA strand. A common example is a cyclobutane pyrimidine dimer, which distorts the local duplex and can obstruct normal polymerases.

Ionizing radiation can damage bases and the sugar-phosphate backbone and can generate single- or double-strand breaks.

Chemical agents can modify bases, crosslink molecules or alter pairing behavior. An agent that increases the frequency of stable DNA sequence changes is called a mutagen.

Damage type matters for repair

Different lesions create different molecular problems:

• a mismatched but chemically ordinary base pair requires identifying which base is incorrect;
• a damaged single base may be removed individually;
• a bulky helix-distorting lesion may require removal of a short DNA segment;
• a double-strand break requires reconnecting two broken DNA molecules or copying information from a homologous template.

Cells therefore use several repair pathways rather than one universal repair enzyme.

DNA damage is best understood as a continual challenge to stored sequence information. Repair pathways recognize particular abnormal structures and use undamaged information—often the complementary strand—to reconstruct the intended DNA sequence.