Of all the proposed causes of ageing, DNA damage remains a leading theory. In addition to the possibly detrimental effect of mutations and chromosomal rearrangements, DNA breaks may promote wide-ranging, age-related changes in chromatin that can result in the abnormal silencing or expression of genes and may, thereby, explain the deterioration of cell function associated with aging, degenerative diseases and cancer on multiple levels. However, the direct physiological consequences of chronic DNA break induction and repair in mammals remains to be elucidated. In this project we will test how transient or chronic DNA breakage affects nuclear organization, gene expression and ultimately cell function in vivo. We have designed a mouse model to induce DNA breaks in a spatially or temporally controlled manner and can, thereby, monitor the effect of ongoing DNA damage in specific organs. One prediction, based on our work and that of others, is that continuous DNA breakage may cause age-related organ degeneration, which can be easily tested in our mouse model. To this end we will cross these mice to established mouse models of age-related (neuro)degenerative diseases. We are further set up to do an extensive analysis of epigenomic changes across the genome in response to chronic DNA damage, thereby testing the hypothesis that DNA damage causes large-scale epigenomic alteration that eventually result in organ dysfunction. Together, this project is expected to provide critical insight into the role of DNA damage beyond its well-established effect on genomic instability, thereby providing a link between the genetic and epigenetic factors associated both with cancer and aging.
