Researchers reporting in Nature hope new insights could lead to safer, more effective cancer drugs.
Two teams of U.K. scientists have independently identified a role for a family of small ubiquitin-like modifier (Sumo) proteins in the repair of double-stranded DNA breaks (DSBs). They suggest the findings could help in the future design of more effective anticancer drugs or reduce the side-effects of current cancer treatments.
At the Wellcome Trust and Cancer Research UK Gurdon Institute and the department of biochemistry at the University of Cambridge, in vitro studies by Stephen Jackson, Ph.D., and colleagues showed that the enzymes which add SUMO onto factors involved in the repair of DSBs are also required for the subsequent modification of some of these proteins by ubiquitin itself. Joanna Morris, Ph.D., and colleagues at the Cancer Genetics Laboratory at King’s College London, looked more closely at the role of SUMO factors in BRCA1 in breast cancer. Both groups report their findings in Nature.
When the two teams analyzed the subcellular localization of SUMO-pathway components in mammalian cells, they found that the E1 SUMO-activating enzyme SAE1, the E2 SUMO-conjugating enzyme UBC9, and the three forms of vertebrate SUMO protein, SUMO1 and the closely related SUMO2 and SUMO3 (SUMO2/3), are recruited to double stranded DNA breaks. Dr. Morris’s team more specifically showed that addition of SUMO to the protein encoded by breast cancer susceptibility gene BRCA1 is necessary to activate its E3 ligase function, which attaches ubiquitin to other DNA repair factors; BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase.
“What’s really striking about our discovery is the capacity these Sumo proteins have to locate and help repair DNA damage as it occurs,” Dr. Jackson notes. “They can also recruit other proteins to help repair double-stranded DNA breaks. We found these proteins can strengthen the cells’ defenses against DNA damage. When their work is done, the SUMO proteins then detach themselves and move on.”
Dr. Morris maintains her team’s findings could represent the first step toward developing new drugs that protect normal cells from the side-effects of chemotherapy or improve the effectiveness of breast cancer drugs. “We discovered how the cells in our body coordinate the difficult task of repairing potentially breast cancer-causing DNA breaks and how they direct BRCA1 to do its job to stop tumors forming.”
Dr. Jackson’s group published their work in a paper titled “Sumo proteins promote responses to DNA double-stand breaks in mammalian cells.” Dr. Morris’ study appears in an article titled “The Sumo modification pathway is involved in the BRCA1 response to genotoxic stress.”
