DNA is constantly sustaining damage from mutagens such as ultraviolet (UV) light, chemicals, and spontaneous deamination. Each cell loses 10,000 bases per day from spontaneous DNA breakdown related to normal body temperature alone. In the absence of repair, these mutations would accumulate and result in tumor formation. Damaged DNA is estimated to cause approximately 80%–90% of cancers in humans.
Damaged DNA sites are repaired chiefly by 2 mechanisms: excision repair and mismatch repair. The processes of replication, transcription, mismatch repair, excision repair, and gene expression are closely coordinated by cross-acting systems. Enzymes that cut or patch segments of DNA during crossing over at meiosis are also involved in DNA repair. Molecules that unwind double-stranded DNA (called helicases) are involved in replication, transcription, and DNA excision repair.
The antioncogene p53 appears to play an extremely important role as the “guardian of the genome” by preventing cells from proliferating if their DNA is irreparably damaged. Levels of p53 increase after UV or ionizing radiation exposure. The p53 gene inhibits DNA replication directly and binds with 1 of the RNA polymerase transcription factors, TFIIH. If the degree of damage is slight, increased production of p53 induces reversible cell arrest until DNA repair can take place. If DNA damage is too great or irreversible, p53 production is massively increased and apoptosis occurs, probably through stimulation of the expression of the BAX gene, whose product promotes apoptosis. Loss of p53 causes cells to fail to arrest in response to DNA damage, and these cells do not enter apoptosis. Thus, mutations of p53 predispose to tumorigenesis.
The gene mutated in ataxia-telangiectasia (Louis-Bar syndrome), a protein kinase called ATM, also appears to be integrally involved in DNA repair, possibly by informing the cell of radiation damage. The ATM gene product associates with synaptonemal complexes, promotes chromosomal synapsis, and is required for meiosis. Individuals with ataxia-telangiectasia have a threefold greater risk of cancer.
Xeroderma pigmentosum is a severe condition in which the functions of enzymes that repair UV-damaged DNA are crippled. Patients with this condition typically have diffuse pigmented anomalies on their sun-exposed skin and are at high risk for basal cell and squamous cell carcinoma, as well as melanoma. Ocular surface cancers (squamous cell carcinoma and melanoma) can also develop in affected patients.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.