BioProject

Cells are constantly under attack by a plethora of DNA damaging agents that arise from both exogenous and endogenous sources. More...

Cells are constantly under attack by a plethora of DNA damaging agents that arise from both exogenous and endogenous sources. To deal with this threat to cell and organism viability, an elaborate set of DNA repair and DNA-damage signaling pathways have evolved. The importance of such processes is illustrated by DNA repair and associated defects causing genomic instability, which in turn can cause cancer and various other human diseases. The importance of chromatin and epigenetics in DNA repair is well established, and changes in chromatin or defects in DNA repair factors can direct and influence the choice of DNA repair pathway. However, it is currently unknown how chromatin and its control may influence the type of mutations and their frequencies, and their distribution in different chromosomal environments on a genome-wide scale. To identify and study the mutational spectra that are characteristic of defects in specific DNA repair and/or chromatin regulatory pathways, we will sequence the genomes of various fission yeast DNA repair and chromatin mutants, along with wild-type yeast controls, that have been exposed to an optimized dose of DNA damage caused by ionizing irradiation. Fission yeast is the model organism of choice for this project, as all major DNA repair pathways are conserved, most chromatin features are shared with higher eukaryotes and the genome is small, comprising around 14 megabases. We anticipate that the data that we generate in fission yeast will not only help us understand DNA repair pathways and genome instability in this organism but will provide with opportunities to subsequently extend such studies to mouse and/or human cells. Notably, genomic instability and epigenetic changes are hallmarks of most cancer types. Therefore, any similarities between the mutation patterns in human cancers and the mutational fingerprints identified in this study, could help to narrow down the specific DNA repair pathways affected in different cancer types, a feature currently unknown for many malignancies. Importantly, this information could indicate how radiotherapy and various DNA-damaging chemotherapies can be best tailored to individual tumours, and might help to significantly extend the range of cancers that can be treated based on synthetic lethality approaches, by specifically targeting the remaining, still functional, DNA repair pathways. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ Less...