The promyelocytic leukemia protein and nuclear domain function in DNA damage signalling and tumour suppression

Cancer arises when cells accumulate genetic changes (mutations) that result from damage to our DNA. These mutations alter the normal regulation of cell growth and division, allowing cancer to develop. A cell normally prevents these mutations by efficiently detecting and repairing damaged DNA. Ironically, DNA damage is also used to kill cancer cells during radiation and chemotherapy. Therefore, it is essential to understanding how a cell responds to and repairs DNA damage if we are to develop better ways to prevent and treat cancer. DNA is found in the nucleus of the cell, which is organized into specialized compartments. One of these compartments is the promyelocytic leukemia nuclear body (PML NB). These bodies are made of a number of different molecules (proteins), and are believed to help prevent cancer from developing because these bodies are disrupted or absent in many types of cancer. For example, PML NBs are disrupted in a type of cancer called acute promyelocytic leukemia, and PML NBs are often absent in the cancer cells that arise in many organs of the body, including the brain, breast, lung and prostate. PML NBs are important to the cell because they help regulate the cell's response to DNA damage but how these bodies carryout this important job is unclear. However, we do know that the different proteins that make up PML NBs can change in response to DNA damage. In addition, we have shown that more PML NBs are produced in response to DNA damage, and that damaged DNA can associate with PML NBs. With these findings in mind, we plan to determine how the association of proteins and damaged DNA with PML NBs is regulated, and what effect this association with these bodies has on the cell's response to DNA damage. These studies will improve our understanding of the role of PML NBs in DNA repair, and will clarify how PML NBs prevent cancer growth. This information will ultimately aid in the development of more effective and safer cancer therapies.