DNA repair

DNA repair refers to the various ways a cell finds and fixes damage in its DNA, the molecule that holds its genetic instructions. When this repair system weakens, the risk of cancer goes up. Inside cells, DNA gets altered constantly—by natural metabolic waste, by radiation from the sun or other sources, by medicines, and by other external factors. This leads to tens of thousands of individual molecular injuries per cell each day. Some DNA changes are also deliberately programmed.

These molecular injuries can warp the DNA structure, interfering with the cell’s ability to read its genes or produce proteins. Others may introduce harmful mutations that affect the survival of future cells after division. Because of this, DNA repair is always active as part of the cell’s broader damage response. When normal repair fails—and when even programmed cell death (apoptosis) doesn’t work—irreparable damage can build up, raising cancer risk.

How much repair a cell performs depends on its type, its age, and its surroundings. A cell that has suffered too much damage or can no longer fix itself effectively may end up in one of three states: it may enter an irreversible dormancy called senescence; it may undergo apoptosis (programmed cell death); or it may start dividing uncontrollably, potentially forming a cancerous tumor. A cell’s ability to repair DNA is crucial for keeping its genome intact and, by extension, for the organism to function normally. Many genes first linked to lifespan have turned out to be involved in DNA repair and protection.

DNA damage comes from both environmental sources and normal cellular metabolism, happening at a rate of 10,000 to 1,000,000 lesions per cell per day. That’s at most 0.03% of the human genome’s roughly 3.2 billion bases, but if unrepaired lesions hit critical genes—like tumor suppressor genes—they can hamper the cell’s function and significantly increase the chance of tumor formation, also contributing to tumor diversity.

Most DNA damage alters the primary structure of the double helix—the bases themselves get chemically modified. These modifications can introduce unusual chemical bonds or bulky add-ons that don’t fit the standard helix, disrupting its regular shape. Unlike proteins and RNA, DNA usually lacks a tertiary structure, so damage doesn’t occur at that level. Instead, it can affect the DNA supercoil and, in eukaryotic cells, the histone proteins that package DNA into nucleosomes.

DNA damage falls into two main categories. Endogenous damage comes from inside the cell, like attacks by reactive oxygen species from normal metabolism (causing spontaneous mutations, including oxidative deamination) and replication errors. Exogenous damage comes from outside agents: ultraviolet radiation (200–400 nm) from the sun or artificial lights; other radiation like X-rays, gamma rays, and particles (electrons, neutrons, alpha particles); hydrolysis or heat; certain plant toxins; human-made mutagenic chemicals (especially aromatic compounds that wedge between DNA bases); and viruses. When damaged DNA is copied before cell division, wrong bases can be placed opposite the damage. Daughter cells that inherit these errors carry mutations that can’t be reversed (except in rare back mutations, like through gene conversion).

Several types of damage arise from internal cellular processes: oxidation of bases (e.g., 8-oxo-7,8-dihydroguanine) and strand breaks from reactive oxygen species; alkylation of bases (usually methylation), such as 7-methylguanosine, 1-methyladenine, or 6-O-methylguanine; hydrolysis of bases, including deamination, depurination, and depyrimidination; bulky adduct formation (e.g., benzo[a]pyrene diol epoxide-dG adducts, aristolactam I-dA adducts); and base mismatches from replication errors, where the wrong base is inserted, skipped, or mistakenly added. Monoadduct damage affects a single nitrogenous base; diadduct damage involves two.

Damage from external agents takes many forms. UV light absorbed directly by DNA triggers photochemical reactions, creating pyrimidine dimers and photoionization that causes oxidative damage. UV-A light mainly produces free radicals, leading to indirect DNA damage. Ionizing radiation from radioactive decay or cosmic rays breaks DNA strands; intermediate levels can cause irreparable damage, leading to replication and transcription errors that may promote cancer or trigger viral interactions, contributing to premature aging and cancer. High temperatures speed up depurination (loss of purine bases from the DNA backbone) and single-strand breaks. For example, thermophilic bacteria living in hot springs at 40–80°C experience depurination rates (about 300 purine residues per genome per generation) too high for normal repair, suggesting an alternative mechanism may be at work.