Break-induced replication: two roles in genome instability

The sequence of our DNA encodes many of our physical and physiological traits. The integrity of our DNA is threatened by sources originating both within and outside of our bodies. These sources can damage our DNA, and if left unrepaired this damage can lead to diseases such as cancer. One of the most severe types of DNA damage is a DNA double strand break, in which both strands of the two-stranded DNA molecule are broken. One of the mechanisms that repairs DNA double strand breaks is break-induced replication (BIR). During BIR the broken DNA searches for an identical DNA sequence on another chromosome (DNA molecule) and copies it to the end of the chromosome. BIR, however, is error-prone and is thought to contribute to cancer initiation and progression. In this thesis I use yeast as an experimental system to model two mechanisms of BIR-initiated genome instability. First, I investigate a BIR-driven process known as alternative lengthening of telomeres (ALT). Telomeres are repetitive sequences at the ends of our chromosomes that shorten each time DNA is copied. Once telomeres reach a critically short length most cells will stop dividing. Other (cancer) cells will use ALT to lengthen these short telomeres, which allows cancer cells to continue dividing and to essentially become immortal. Second, I investigated the DNA damage that occurs when DNA repair by BIR is interrupted before completion. Modelling these processes in yeast provides insight into cancer development and progression.