- DNA lesions are structural alterations or damages in the DNA molecule that disrupt its normal integrity, stability, or coding potential. Unlike mutations, which are permanent changes in the DNA sequence, lesions are initial forms of damage that may or may not be repaired correctly by cellular mechanisms. They can arise spontaneously during normal cellular processes or be induced by external agents such as radiation, chemicals, or toxins. These lesions are important because they compromise the fidelity of DNA replication and transcription, and if left unrepaired or misrepaired, they can give rise to mutations, genomic instability, and disease.
- There are many different types of DNA lesions, each with distinct causes and consequences. Base modifications are among the most common, resulting from oxidative stress, alkylation, or spontaneous hydrolytic reactions. For example, depurination (loss of a purine base) and deamination (conversion of cytosine to uracil) are frequent spontaneous lesions. Single-strand breaks can occur when the sugar-phosphate backbone is damaged, while more severe double-strand breaks result from ionizing radiation or replication stress and are especially dangerous because they compromise chromosomal integrity. Other lesions include thymine dimers, which form when ultraviolet (UV) light induces covalent crosslinks between adjacent pyrimidine bases, and DNA crosslinks, where two strands of DNA or DNA and proteins become chemically bound, blocking replication and transcription.
- The biological consequences of DNA lesions depend on their type and whether they are repaired. Some lesions can block replication or transcription, stalling essential cellular processes. Others can lead to mispairing during DNA replication, which results in permanent mutations. Accumulation of DNA lesions is strongly associated with aging, as DNA repair capacity declines over time, and with diseases such as cancer, where unrepaired or incorrectly repaired lesions cause uncontrolled cell growth due to genomic instability.
- Cells have evolved a wide array of DNA repair mechanisms to counteract lesions and maintain genome stability. Base excision repair (BER) corrects small, non-helix-distorting lesions such as depurination or oxidation. Nucleotide excision repair (NER) removes bulky lesions, including thymine dimers caused by UV radiation. Mismatch repair (MMR) fixes replication errors that escape proofreading, while double-strand break repair pathways, such as homologous recombination (HR) and non-homologous end joining (NHEJ), restore chromosomal continuity. When DNA lesions are too extensive or irreparable, cells may undergo apoptosis (programmed cell death) to prevent the propagation of damaged DNA.
