Inhibition of 53BP1: Potential for Restoring Homologous Recombination in Ovarian Cancer Cells
Abstract
Our genes are made up of two very long strands of DNA that are tightly packed around histones to form structures called chromosomes. We have 23 pairs of these chromosomes, and they are found in every cell in our body. Our genes dictate the production of complex molecules called proteins that play multiple essential functions in our body. There are many kinds of proteins. Histones are one kind; enzymes are another. Enzymes carry out the numerous chemical reactions that constantly take place in our cells and are necessary for life. Thus, it is important that our genes or the DNA strands in our genes remain intact. When the DNA strands are broken and not repaired, our chromosomes become destabilized, our genes are altered (also called mutated), and abnormal proteins are produced. This condition is very toxic and often leads to cancer. A prominent example is the Brca1 gene that is responsible for producing the BRCA1 protein. When the Brca1 gene is mutated, it increases a person s risk of developing ovarian and breast cancer. Our body is armed with different ways of repairing the DNA double-strand breaks (DSBs). One way is called homologous recombination or HR. HR is regulated by BRCA1 and another important protein called 53BP1. The effects of BRCA1 and 53BP1 are opposite. BRCA1 activates HR while 53BP1 inhibits HR. Studies have shown that when the Brca1 gene is disrupted in mice, it promotes formation of tumors in mice. Moreover, when the Brca1 gene and another gene called p53 are inactivated in mice, the mice develop ovarian tumors. Because these mice have abnormal BRCA1 due to a disrupted Brca1 gene, they also have abnormal or defective HR activity. Surprisingly, when the 53bp1 gene that controls the production of 53BP1 protein is removed from these animals, the mice do not develop tumors. The most likely explanation is that since 53BP1 is known to inhibit HR, removing 53bp1 gene reactivates HR and corrects the abnormal HR activity caused by mutations in Brca1. Our idea is to investigate the possibility that inactivating the 53BP1 protein would reactivate HR and prevent ovarian cancer in people who have a mutated Brca1 gene. To test this hypothesis, we propose a basic discovery research approach where we examine how our cells can naturally inactivate 53BP1. One path to the inactivation or inhibition of 53BP1 is to prevent this protein to go to the site of DNA damage. In other words, we are exploring natural regulatory mechanisms that our cells already have to prevent 53BP1 to go or be recruited to DNA damage sites. From previous studies by our group and by others, we know that the recruitment of 53BP1 requires that it recognize two chemical signals near the DNA breaks in chromosomes. These two signals, called ubiquitylation and methylation, are present in histones. Recently, it was suggested that a protein called RNF169 inhibits 53BP1 recruitment. We also identified a new protein called RNBP3 that prevents 53BP1 from recognizing the methylation signal. By understanding how natural proteins in our body can under certain conditions prevent 53BP1 from recognizing the ubiquitylation or methylation signals, we may be able to devise ways to inhibit the recruitment of 53BP1. For example, we could design small molecules that would prevent 53BP1 from recognizing the ubiquitylation or methylation signals. Such small molecules would prevent 53BP1 to go to DNA damage sites and would therefore inhibit the HR inactivating role of 53BP1. We believe that in the long term such molecules could be developed into drugs. By inhibiting 53BP1 recruitment, those drugs would restore HR activity and prevent ovarian cancer in individuals who have mutations in the Brca1 gene. In summary, the short-term outcome of the proposed basic research will be a deep mechanistic understanding of the natural regulatory inhibition of 53BP1 recruitment to DNA damage sites in cells. By understanding this natural inhibitory mechanism,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610391
Entities
People
- Maria Victoria Botuyan
Organizations
- Mayo Clinic
- United States Army