What is DNA lesions? — Biology

Definition 3.1 University Biology — Year 3 · Chapter 3 — Genome Stability: DNA Damage, Repair and Recombination

A lesion is any chemical alteration of DNA away from the four normal bases correctly paired on an intact backbone. Spontaneous lesions arise from the chemistry of water and oxygen: depurination, hydrolysis of the bond between a purine and its sugar, leaving an abasic site (about $10^{4}$ per cell per day); deamination, which turns cytosine into uracil, 5-methylcytosine into thymine, and adenine into hypoxanthine (a few hundred per day); oxidation by reactive oxygen species, chiefly to 8-oxoguanine, which pairs with adenine as readily as with cytosine; and replication errors, a misincorporated or slipped base. Environmental lesions include the cyclobutane pyrimidine dimer and the 6-4 photoproduct made by ultraviolet light between two adjacent pyrimidines; alkylated bases from alkylating agents (O $^{6}$ -methyl- guanine pairs with thymine); bulky adducts from aromatic hydrocarbons and aflatoxin; interstrand cross-links from cisplatin and nitrogen mustards; and the single- and double-strand breaks made by ionising radiation, about $1000$ single-strand and $30\text{ to }40$ double-strand breaks per cell per gray.

Examples

Example 3.3 (Lesions against mutations)

A human cell of $6.4\times 10^{9}$ base pairs dividing once a day accumulates on the order of $10^{4}$ – $10^{5}$ lesions a day and about $6.4\times 10^{9}\times 10^{-10} \approx 0.6$ new mutations per division: fewer than one lesion in ten thousand survives to become a permanent change. The rest are repaired before replication reads them, and the rate of survival to mutation — not the rate of damage — is what selection has minimised. The same arithmetic shows why the number of mutations in a tumour or in the sperm of an older father counts divisions: the mutations a cell carries are, to first order, the divisions it has undergone times the error per division.

Example 3.9 (Why xeroderma is a disease of the fork)

A dose of sun leaves $N = 10^{5}$ pyrimidine dimers in a keratinocyte. With a nucleotide excision half-life of $2\,\mathrm{h}$ ( $k = 0.35\,\mathrm{h}^{-1}$ ) and a fork arriving after $8\,\mathrm{h}$ , $N e^{-kT} = 10^{5}\times e^{-2.8} \approx 6000$ dimers are still there to be copied; with the near-absent repair of an XP cell ( $k \approx 0.01\,\mathrm{h}^{-1}$ ), $92\,000$ are. Each dimer met by the fork is bypassed by translesion synthesis (below), which is error-prone: the patient’s mutation load per division is fifteen times the normal one, and the skin cancers follow in childhood. The cure that works is to keep $N$ small — total avoidance of ultraviolet light.

Example 3.13 (Synthetic lethality: BRCA and PARP)

Women who inherit one defective copy of BRCA1 or BRCA2 have a lifetime risk of breast cancer of $50\text{ to }80\,\%$ ; the tumours arise in cells that have lost the second copy and can no longer do homologous recombination. Such cells repair their double-strand breaks by end joining alone and accumulate rearrangements. They also acquire a specific weakness. Single-strand breaks, some $10\,000$ a day, are repaired by a route that needs the enzyme PARP; when PARP is inhibited by a drug, single-strand breaks persist to S phase, where a fork converts each into a double-strand break with only one end — repairable only by recombination. A normal cell, with one good BRCA allele, copes; the tumour cell dies. Two defects, each harmless alone, are lethal together: the drug kills by synthetic lethality, and spares the patient’s other cells.

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