Dr. Martin Kupiec
Tel Aviv University
After completing a Ph.D. thesis at the Hebrew University of Jerusalem, I went to the laboratory of Prof. Tom Petes in Chicago to carry out my post-doctoral training. Tom was then a young researcher, doing exciting molecular biology work using yeast cells. Among other subjects running in the lab, they were investigating the biology of telomeres, and they even had mutants that had extremely short telomeres, but were alive.
These mutants (tel1) were later found to be defective in the yeast version of the central ATM gene. I was attracted to the subject, as even then it was obvious that telomeres (the ends of the chromosomes) play important roles in preventing cancer, and in aging. However, when I arrived to Chicago, and met the other post-doctoral fellows, I was told of an amazing result they had obtained: If a sequence of DNA is present at a certain location in the genome, and one introduces (by genetic engineering) a second copy of that sequence on another chromosome, the two sequences can recombine, exchanging information (pieces of DNA go from one location to another).
This has both positive and negative implications: on one hand it may “erase” mutations that appeared in one of the copies; on the other, it may create chromosomal aberrations, such as translocations, inversions or deletions. I got so intrigued by this result that I abandoned my original plan of working on telomeres, and started to ask questions about this seemingly magic process in which two small regions of the genome find each other to exchange pieces of DNA.
I asked two main research questions: the first one was mechanistic: genomes are huge; how do two short pieces of DNA find each other in order to exchange information? How do these things happen? What proteins are in charge? This line of work produced, with the years, a lot of information about how cells repair broken DNA, and it turned out that this is the mechanism that does not work in people carrying a mutation in the BRCA1 or BRCA2 genes.
My second line of investigation had to do with genome composition: in most genomes there are repeated sequences. In the human genome, for example, there are 2 million “Alu sequences”,
and even in a simple genome, like the one of yeast, there are “Ty elements”, repeated units that cover ~6% of the genome. They should recombine all the time, as there are 60 copies of them. When I measured the rate at which these exchanges occur for a single gene, or for this family of 60, I found that there were less events for the large family together, than for a single pair. This implies that there are mechanisms that prevent recombination between repeated sequences.
In October 1988 I returned to Israel, eager to open my own laboratory at Tel Aviv University. I sat down to write grant applications, and the first one I wrote (in December 1988) was to the ICRF. Reading again the proposal, almost 30 years later, I can see that what I proposed to do then is a roadmap of my future career: I proposed to set a genetic screen to find mutants that affect recombination between repeated sequences, and to investigate the mechanism that creates them. Indeed, with the help of ICRF, I carried out genetic screens and found several mutants that have high levels of recombination between Ty elements. This screen also identified ELG1 (enhanced levels of genomic instability 1), a gene that plays central roles in DNA handling, and therefore in its repair and compaction (large amounts of DNA should fit into the tiny cellular nucleus).
My current ICRF grant allows us to continue our investigation of this interesting gene, whose human counterpart acts as a tumor-suppressor. Moreover, it turns out that Elg1 also helps maintain telomere length, and so I have returned also to the exciting field of telomere biology.
Thus, 27 years later, I can say with pride that we have made much progress, and ICRF keeps being a continuous source of support and encouragement, for which I would like once more to say: Thank you!