BioWorld International Correspondent
Scientists have searched and searched to find genes in nematode worms and other lower organisms that are similar to the human tumor-suppressor gene known as BRCA1, always without success. But now, a team of researchers from the UK, Germany and the U.S. has found one.
The discovery is good news for researchers studying the genetics of breast and ovarian cancer, because it will speed up analysis of what molecules BRCA1 interacts with. In turn, that information could help in the development of new treatments for those cancers.
Simon Boulton, research scientist at Cancer Research UK, the UK's largest cancer research charity, told BioWorld International: "We can do experiments much more quickly in nematodes than in mammalian cells, so we think we will be able to accelerate the understanding of how these genes function at the molecular level, and define both the genetic and the biochemical pathways in which these genes function."
He and his colleagues hope that will lead to a better understanding of what goes wrong when BRCA genes are mutated and how those defects lead ultimately to breast or ovarian cancer.
The researchers at the Cancer Research UK London Research Institute, where Boulton works, have made further discoveries since submitting their paper for publication. Boulton said he could not speak about those findings in detail, but added that they provided "completely new mechanistic insights into the role of BRCA1 and related proteins in the repair of double-stranded DNA." He expects papers reporting those findings to appear within months.
A paper outlining the current findings is published in the January issue of Current Biology. Its title is "BRCA1/BARD1 orthologues required for DNA repair in Caenorhabditis elegans."
The genes BRCA1 and BRCA2 were discovered several years ago, but despite major research efforts by teams of scientists around the world, little is known about their function other than that they play a role in repairing damaged DNA. Detailed genetic analysis of their function, of the kind normally carried out in yeast, fruit flies or worms, was not possible because it appeared that the genes were only present in complex eukaryotes, from frogs to mammals.
Scientists knew that the protein encoded by BRCA1 is normally found linked to one called BARD1, which stands for BRCA1-associated ring domain protein. Boulton and his colleagues discovered, while scrutinizing the genome of the nematode worm (Caenorhabditis elegans), that one of the worm's genes was similar to that encoding BARD1.
Boulton said: "Given that BARD1 in humans interacts with BRCA1, the presence of BARD1 in C. elegans immediately suggested to us that there should be a BRCA1 as well, even though no one had seen it previously."
Using an assay designed to detect proteins that interacted with BARD1, they discovered a protein equivalent to the human BRCA1. Earlier searches, which had used a computer algorithm to predict where the genes were in the C. elegans sequence, had failed to pick up the worm's BRCA1 gene because part of its coding sequence had been missed by the algorithm.
Further studies showed that the worm's BARD1 and BRCA1 proteins interact with each other, just as they do in humans.
To test whether the BARD1 and BRCA1 genes in the worm were involved in DNA repair, the researchers used a technique called RNA interference to separately switch off the genes, while leaving all other genes unaffected.
They found that many of the germ cells died after DNA damage. Boulton said: "Our results showed that these worm genes are involved in the DNA repair process and are essential for surviving DNA damage."
Questions that the team is tackling include how the worm proteins function in DNA repair, whether they have enzymatic activity and, if so, what are their substrates and how do they alter those substrates. After that, they will want to know to what extent the findings are directly transferable to mammalian cells.
The team also identified several other proteins that interacted with BARD1 in C. elegans. When the genes encoding those proteins were switched off, the worms showed similar defects to those animals lacking BARD1 or BRCA1.
"This suggests that they participate in the same genetic pathway as BRCA1, and by analogy we think that the mammalian equivalents of these new proteins may also play a role in this pathway in mammalian cells," Boulton said.
If that turns out to be true, Boulton and his colleagues plan to begin screening panels of tumors to find out if the cells contain any defects in the genes encoding the newly identified proteins.