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. The penetrating radiation from ultraviolet light induces DNA lesions in skin cells that can block DNA replication and cause mutations that develop into cancer. One way in which the body copes with this damage involves specialized DNA polymerases to bypass such lesions. DNA polymerase η (Polη) does this by replicating DNA containing thymine dimers — and inactivation of this enzyme results in a variant of the skin disease xeroderma pigmentosum and a high incidence of skin cancer. Two groups have now determined the crystal structure of Polη. The structures — one of the yeast enzyme and one of the catalytic domain of the human enzyme — show how the bulky thymine dimer is accommodated in an unusually large active site, and how the lesion is stabilized by interactions not found in other polymerases. Missense mutations from xeroderma pigmentosum patients are found to disrupt the polymerase's ability to maintain the damaged DNA in normal B form. In the accompanying News & Views, Suse Broyde and Dinshaw Patel discuss how the structure of Polη compares with those reported for other Y-family DNA polymerases.