What is Translesion synthesis? — Biology

Definition 3.10 University Biology — Year 3 · Chapter 3 — Genome Stability: DNA Damage, Repair and Recombination

When a fork meets a lesion that has not been repaired, the replicative polymerase stalls. Translesion synthesis (TLS) calls in a specialised polymerase with a roomier active site and no proofreading — Pol $\eta$ for pyrimidine dimers, Pol $\iota$ , $\kappa$ , $\zeta$ and Rev1 for other lesions — which inserts a few nucleotides opposite the lesion and steps aside. Pol $\eta$ puts two adenines opposite a thymine dimer, which is usually right; the others are often wrong. TLS trades accuracy for the survival of the fork, and is the source of most ultraviolet-induced mutations. The variant form of xeroderma pigmentosum (XP-V) has intact excision repair and lacks Pol $\eta$ : the dimers that escape excision are bypassed by the more error-prone polymerases, and the cancers follow.

Examples

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.

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