2010/03/15

To mutate or not to mutate: that's the question

Palms, fingers and thumbs are not just parts of the human body. They are also terms used to describe the structural elements that make up the catalytic core of fundamental enzymes such as DNA polymerases. These enzymes are present across the three kingdoms of life, Eukarya, Archaea and Bacteria (but also encoded by some viruses), and are involved in DNA replication, a process that allows the polymerisation of a new DNA fragment by the readout of a DNA template. The fidelity of this readout and copying mechanism, essential for the proper functioning of the cell, is affected by several factors; one of them is the DNA template integrity. Indeed, DNA can suffer lesions, for example caused by the interactions with aromatic amines, carcinogenic and mutagenic compounds that can be found in cigarette smoke.

Using X-ray crystallography Rechkoblit et al. have revealed the mechanism through which a member of the low-fidelity polymerases group (Y-family) called Dpo4 by-passes the damaged DNA (in the case study a 2-aminofluorene aromatic amine covalently linked to a guanine base of a DNA fragment) producing either a correct newly synthesized strand or a mutated one. In the mutagenic case this mechanism relies on the polymerase's domains "little finger" and "thumb" tuning their interactions to the large aromatic amine rather than the misaligned base pairs. With this study Rechkoblit et al. have provided a rationale for how lesions in the DNA template turn into mutated products during polymerisation activity, a sequence of events that can lead to the development of cancer.