Spotlight on

Dr. Jeffrey Strathern
Chief, Gene Regulation and Chromosome Biology Laboratory
Principal Investigator,Genome Recombination and Regulation Section

Spotlight Archive

How does basic research, focused on seemingly simple organisms like yeast and bacteria, tell us about the origins of cancer? Answer: The unifying principles of biology allow the use of model organisms to provide important paradigms. 

Whenever the fidelity (i.e., accuracy) of any biological process goes awry, it may contribute to an increase in the DNA mutation rate. High mutation rates, in turn, contribute to tumorigenesis. The research conducted in Dr. Jeffrey Strathern’s Genome Recombination and Regulation Section provides a good example of how an examination of those biological processes that are common to all living organisms serves as a foundation for further studies. Dr. Strathern and his colleagues use the yeast model system (Saccharomyces cerevisiae) to study the fidelity of genetic replication and recombination.

Why Yeast?

So, why exactly do Dr. Strathern and his colleagues use the yeast model system? In the field, it is called the “Awesome Power of Yeast Genetics.” Dr. Strathern calls it the power of toothpicks and velvet, the basic tools for manipulating yeast mutants. The ability to grow yeast as either haploid (one copy of each chromosome) or diploid cells (two copies) facilitates the isolation and characterization of mutations. The field of yeast genetics, which has been around for more than 50 years, has produced a large community of researchers. This community, in turn, has built a vast collection of knowledge, tools, and literature that other scientists draw upon for their own investigations. For example, S. cerevisiae was the first eukaryotic organism to be fully sequenced, and Dr. Strathern was part of a consortium that made deletion alleles of all of the yeast genes. 

Dr. Strathern believes that where applicable, biological problems should be approached first in yeast. “A lot of the research tools available in yeast will get you to the basic problem faster than anywhere else,” he says. As a eukaryote, the mechanisms in yeast that govern cell cycle, gene expression, genome replication, chromosome segregation and recombination are similar and, in some cases, identical to those found in higher eukaryotic organisms, including humans. Toothpicks and velvet have been used to isolate mutations that identified key genes involved in each of these processes.

The Importance of Being Accurate

Dr. Strathern and his colleagues use yeast cells to study the fidelity of genetic replication and recombination events. Most organisms make about one mistake per duplication of their DNA. Species with more DNA make fewer mistakes per million bases replicated. How do organisms maintain this accuracy and what are the consequences when these mechanisms fail? “One of the major things that has been learned about cancer from model organisms is that there are mechanisms for checking on the fidelity of DNA replication,” explains Dr. Strathern. When those systems fail, you have a huge error rate, which means you have a huge tumor rate. In fact, the enzymes involved in detecting errors and in DNA damage repair were first worked out in bacteria and yeast. Several of the genes that we have shown to influence the fidelity of DNA damage repair, have related genes involved in avoiding tumorigenesis in humans. Some of those human genes carry names that reflect their initial discovery in yeast.

Error-Prone Polymerases:  DNA Damage Control

One of Dr. Strathern’s ongoing investigations focuses on the role of error-prone polymerases in normal biological processes. During replication, polymerases use the strands of DNA as templates to create complementary DNA strands.  If the DNA is damaged and is not repaired, the cell will die. Error-prone polymerases (also called translesion polymerases) can actually copy these damaged templates. Error-prone polymerases can’t reproduce the original DNA sequence perfectly, but they can at least repair the chromosomes. Dr. Strathern’s lab was the first to show that error-prone polymerase plays an important role in recombination in yeast and proposed that these polymerases might have a role in the somatic hypermutation of immunoglobulin genes in mammals. 

A role for error-prone polymerases in creating the diversity of antibodies has now been established. These error-prone polymerases could elevate the overall mutation rate, hence the tumor rate among cells that have turned on this process. Dr. Strathern’s lab is studying how these error-prone polymerases are targeted to specific regions of the genome. Another of the lab’s projects is exploring whether the higher error rate that happens during meiosis in yeast cells is also dependent on these error-prone polymerases. By studying this phenomenon in yeast, they hope to provide a paradigm for what happens during meiosis in other organisms, including humans.

Palindrome Sequences: A Key to Understanding Tumor Cells?

Tumor cells frequently amplify their genes via the formation of DNA palindromes. Palindromes occur when a sequence of DNA is duplicated and the duplicated sequence is then joined head-to-head. Some tumor cells are loaded with these palindromes, but they are nearly impossible to clone, sequence, and analyze in most organisms. However, Dr. Strathern’s lab recently discovered a mutant yeast strain that allows the stable formation of palindromes. They also developed an assay that allows them to study the formation and analyze the mechanism(s) involved in this process. One of Dr. Strathern’s colleagues, Dr. Alison Rattray, has even developed a technique for sequencing palindromes.

Although the human genome has largely been sequenced, many mysterious gaps exist in the sequence. Dr. Strathern believes that some of these gaps may actually be palindromes. “There are already a couple candidates for parts of the human genome that look like they might be palindromes,” says Dr. Strathern. The lab hopes to be able to clone these human DNA palindromes into the mutant yeast strain and then sequence these sections to help identify exactly what they are. This work, in collaboration with Dr. Susanna Lewis (Hospital for Sick Children Research Institute in Toronto) will attempt to fill in these blank sections of the human genome.

The Accuracy of RNA Synthesis:  Solving a Mystery

Cells use RNA to turn DNA information into a variety of biological functions. RNA polymerase reads the information stored in the DNA and then makes makes a temporary RNA copy of the original DNA—a process known as transcription. What controls the accuracy of RNA transcription and how accurate is this process? Because the RNA copy is a temporary template that is quickly discarded, what happens when a mistake occurs and how do you go about studying such short-lived molecules? “This is a huge, 40-year-old problem in basic biology that has never been solved. Almost nothing is known about the fidelity of RNA polymerases or what happens when errors occur,” explains Dr. Strathern. The problem is an important one because it could be that inaccurate (i.e., low fidelity) RNA transcription might contribute to tumorigenesis. In recent years, Dr. Strathern’s lab has developed several assays that may help identify how low-fidelity RNA polymerases behave during this process.

The Next Jacques Cousteau?

Dr. Strathern’s interest in science began when he was young. His father, who is a minister, also has a degree in biology and introduced Dr. Strathern to science and the scientific method. “By the time I was in high school,” he recalls, “I thought I was going to be the next Jacques Cousteau.” While pursuing studies in marine biology at the University of California, San Diego, Dr. Strathern discovered that he had a talent for designing experiments. And, although marine biology was interesting, the field was limited to observation rather than experimentation.  Scuba diving and fishing are still his favorite recreation. Encouraged by Paul Saltman, he decided to change careers and went on to study molecular biology and genetics under the mentorship of Ira Herskowitz. 

One of Dr. Strathern’s guiding principles over the course of his career derives from Dr. Herskowitz’s rule, “‘Never let one fact stand in the way of a good model.’ You need to sometimes question what people believe in order to understand what you really don’t know,” Dr. Strathern advises.

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