DNA repair: How to accurately bypass damage

Abstract

Ultraviolet radiation can cause cancer through DNA damage — specifically, by linking adjacent thymine bases. Crystal structures show how the enzyme DNA polymerase η accurately bypasses such lesions, offering protection.

Figure 1. Accurate lesion bypass by Polη

a, Ultraviolet (UV) radiation catalyses covalent linkages between two adjacent thymine (T) bases in a DNA strand so that they form a distorting mutagenic lesion, the T–T dimer. Backbone phosphorus, yellow; oxygen, red; nitrogen, dark blue. b, Biertümpfel et al. report the structure of human Polη in a ternary complex containing dATP correctly positioned opposite the 3′ base of the thymine dimer in the template strand. This structure reveals an active site (the area within the dashed lines) that is enlarged compared with other Y-family polymerases and that accommodates the two covalently linked thymine bases to permit ‘Watson–Crick’ hydrogen bonding with the dATP, which is oriented for catalysis mediated by two metal ions (purple spheres). Silverstein and colleagues present a related ternary complex of yeast Polη, uncovering a remarkably similar strategy for thymine-dimer bypass (not shown). Thymine dimer, orange; template bases, blue; primer bases, green; incoming nucleotide, white. c, The crystal structure of human Polη is shown in a ternary complex in which the DNA has been replicated past the thymine-dimer lesion by the addition of two nucleotides (A). Unlike other lesion-bypass polymerases, Polη contains a molecular splint — a continuous protein interface between the core (palm and finger) and little finger domains, which cannot be seen in this view — that holds the growing duplex in its normal B-DNA conformation, allowing efficient and accurate extension past the thymine dimer.