By Dean A. Haycock
Special To BioWorld Today
After all the headlines in recent years announcing first the identification of individual genes and then the sequencing of entire genomes, biologists and biology watchers must happily anticipate all the headlines that will announce the function of many of the genes sequenced so far.
It has been six years since the breast cancer susceptibility gene, BRACA1, was identified, for example. While it is still not known exactly what the gene does, researchers are making progress assigning a function to it. Mutations in the gene turn up in half of all patients with breast cancer and in most families with inherited breast and ovarian cancer. BRACA1 is a tumor suppressor gene. When tumor suppressor genes such as BRACA1 don't work properly, they promote tumors. (Another type of cancer gene, the oncogene, works the opposite way: Oncogenes promote cancer when they gain function or are overexpressed.)
Researchers are convinced that BRACA1 has something to do with repairing damaged DNA and regulating the progression of the cell cycle following DNA damage. Thus, it makes sense that mutations in BRACA1 could lead to the propagation of DNA errors and cancers. But no one knew how the tumor suppressor was activated or how the protein knew it was time to get to work.
A paper in the March 9, 2000, issue of Nature, "hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response," helps explain how the activity of the tumor suppressor is controlled. The hCds1 mentioned in the title refers to the human form of the Cds1 kinase, an enzyme that attaches phosphates to its substrates and so changes their properties. Co-author Jay Chung is an investigator in the Laboratory of Molecular Hematology at the National Heart, Lung and Blood Institute, National Institutes of Health in Bethesda, Maryland. He and his colleagues found that the BRACA1 protein and Cds1 have a close relationship. They cluster together in the nucleus until some DNA-damaging stimulus, such as gamma irradiation, damages the cell. Then BRACA1 and Cds1 split up, but not before the tumor suppressor is phosphorylated on one particular amino acid ¿ a serine located at position 988 to be exact.
Scientists knew that BRCA1 was located in the nucleus, that it could be hyperphosphorylated and that it was dispersed following DNA damage. They did not know, however, if the phosphorylation and dispersion of BRACA1 were directly linked to its suspected role in DNA repair. "BRACA1 was known to be phosphorylated before," Chung told BioWorld Today. "The function of that phosphorylation has not been demonstrated in the past."
Cds1 Kinase Regulation Follows DNA Damage
Now, Chung and his colleagues have demonstrated that human Cds1 kinase regulates BRCA1 function following DNA damage. Their data indicate that not only is phosphorylation of BRCA1 at serine 988 required for the release of BRCA1 from the kinase, but that it also affects the ability of BRCA1 to promote survival in cultured cells after their DNA has been damaged. This effect was demonstrated in cultured HCC1937 cells that have a BRACA1 mutation.
The authors believe that BRACA1 has a very important function in DNA damage recognition and repair. "We have made one connection that tells BRACA1: 'There is DNA damage, go repair it,'" Chung said. "But we think there are a number of other communication lines to BRACA1." They suspect other kinases and other kinds of stress might also be involved. "Furthermore, we want to know what is the function of BRACA1. It is still not clear what happens when you tell BRACA1 there is DNA damage."
Another unanswered question surrounding this tumor suppressor concerns its distribution in the body. "BRACA1 is expressed in all tissue types," Chung explained. "If it is important for DNA damage repair in all tissue types, why do the carriers of BRACA1 mutations get only breast and ovarian cancer? That is another puzzle right now."
One Goal Is Increasing Sensitivity To Chemotherapy
While much more basic research is required to learn the details of BRACA1's exact role, regulation and mechanism of action, potential therapeutic applications of the research are clear to researchers like Chung. "Conventional chemotherapy consists mostly of DNA-damaging agents. One of the ways one can make tumor cells more sensitive to conventional chemotherapy might be by making them even more sensitive to DNA damage itself. I guess one practical implication of this type of research is that one day we may be able to design drugs that block the ability of the [cancer] cell to repair DNA damage and hence make cancer cells even more sensitive to conventional chemotherapy."
Another recent development that could improve understanding the roles of BRACA1 and Cds kinases in breast and ovarian cancer comes from studies of patients with Li-Fraumeni syndrome. "This is a well-known syndrome because these patients are born with a p53 mutation," Chung said. p53 is another tumor suppressor gene. It, too, regulates cell responses to DNA damage and other stresses. Approximately half of all human tumors show loss of p53 function.
"These patients get all kinds of cancers," Chung continued. "[But] a certain percentage of Li-Fraumeni syndrome patients do not have p53 mutations. People have been wondering what is causing the syndrome in these people. It turns out that some of these variant Li-Fraumeni patients have mutated Cds1 kinase, the kinase that phosphorylates BRACA1. It turns out that a mutation in Cds1 may have similar manifestations as p53 mutations. These patients get breast cancer as well."