Project 171797

It is now well accepted that cancer is caused by DNA alterations and mutations in a group of cancer related genes. DNA repair plays an important role in protecting cells from such DNA damage and mutation and is considered as the genome guardian. Defects in many DNA repair genes have been linked to cancer and other human diseases. We recently contributed to the discovery of a new mechanism collectively called DNA damage tolerance, in which damaged DNA is not repaired, but continued DNA synthesis and cell division is allowed in the presence of damaged DNA. Using yeast as a model, we have made significant progress in our understanding of how this process occurs, which genes are involved, and the consequences if one of these functions is missing. More specifically, we recently discovered a centralized system to coordinate three relatively independent damage tolerance pathways. In the current proposal, we wish to continue this investigation and pay special attention to how each pathway operates and how they are jointly coordinated. Since each pathway will lead to different consequences of genomic instability, understanding the above regulatory mechanisms will help to assess the risk of cancer. Since almost all the genes we are studying in this proposal have human counterparts, we are certain that the knowledge obtained from this study will be applied to develop diagnostic and therapeutic tools for cancer.