Environmental Factor, February 2007, National Institute of Environmental Health Sciences
DNA Repair Expert Delivers Distinguished Lecture
By Eddy Ball
Geneticist James Haber, Ph.D., presented the most recent talk in the 2006-2007 NIEHS Distinguished Lectures series at 11:00 AM on January 9 in Rodbell Conference Center. Haber is the Abraham and Etta Goodman Professor of Biology and director of the Rosenstiel Basic Medical Sciences Research Center at Brandeis University. His lecture addressed "Checkpoint Responses and Repair of a Broken Chromosome."
Laboratory of Molecular Genetics Staff Scientist Dmitry Gordenin, Ph.D., sponsored Haber's talk. In Gordenin's introduction, he described Haber as "the centerfold of molecular genetics" and a leading authority on the subject of double-strand DNA breaks (DSBs). "To a large extent we owe the current knowledge about the molecular mechanisms of DSB-repair to the work of the Haber lab," Gordenin said. "[Haber's] experimental approach and the system itself have been very successfully utilized in a number of laboratories."
Haber's lab uses yeast, specifically the budding yeast, Saccharomyces cerevisiae, as an experimental organism to study DSBs in vivo. This yeast possesses many characteristics of more complex organisms, yet offers the advantages of studying a simpler, unicellular living system. The repair process is well conserved through evolution, and studies of DNA repair homologs in yeast and other simple organisms can help scientists understand the process in human cells.
Radiation, reactive oxygen species and replication errors or "nicks" constantly threaten damage to DNA. DSBs are the most toxic DNA lesions and DSB-repair is the last line of defense against DNA damage to the genome. To survive and reproduce, cells must assess damage to DNA and then repair it or trigger apoptosis to eliminate damaged cells and protect the viability of the organism. Studying the mechanisms of repair of DSBs in this budding yeast - and especially the defects in repair of chromosome damage or defects in what is known as the DNA damage checkpoint - can offer insight into what Haber described as "the incredible genome instability" of cancer cells.
To repair DSBs, cells respond by activating the DNA damage checkpoint, which includes the induction and repression of many genes. The checkpoint triggers an arrest in the cell cycle to allow the organism to repair the damaged chromosome by searching initially intra-molecularly and, then if necessary, extra-molecularly through the entire genome, for competent material to make the repair.
When the repair has been completed successfully, the checkpoint arrest signal is extinguished and reproduction continues as cells re-enter the cell cycle. Checkpoint defects cause a substantial problem in multi-cellular organisms because damaged chromosomes and genetic instability can result in tumors. An understanding of checkpoint function can shed light on the mechanism of tumor formation and cancer predisposition and ultimately may provide insights into new therapeutic targets for cancer treatment.
Haber and his colleagues have made significant progress toward understanding the roles of DNA intermediates that arise during the repair of DSBs by recombination, as well as during meiosis and mating type switching. His lab has established the relative importance of several pathways for non-homologous end-joining in yeast and shown their similarity to those in mammalian systems. However, despite the advances his lab has made in elucidating DSB repair, Haber admitted, "Every time you think you understand these processes, like resection, something else gets in the way."
In the course of his career, Haber has received many honors for his work. In 2005, he was elected a fellow of the American Association for the Advancement of Science (AAAS), and for over a decade he has been a fellow of the American Academy of Microbiology. Several funding organizations, including the Sloan Foundation, the Guggenheim Foundation and the National Science Foundation, have provided support for his research. Individually and with colleagues worldwide, he has published over 200 articles in peer reviewed journals, and he serves on the editorial boards of several important journals in his field, including Molecular and Cellular Biology, DNA Repair, PLoS Biology and PLoS Genetics.
An Obligation that Began a Career in Genetics
In a "Perspectives" commentary published in the July 2006 issue of the journal Genetics, Haber described the turn of events that thrust him into the field of genetics. "When I arrived at Brandeis [as an assistant professor of Biology]," he explained, "I was assigned to teach genetics, a subject I had never studied as either an undergraduate or a graduate student."
Luckily for him, the university had teamed Haber with master geneticist Jeff Hall, who guided the new teacher through Drosophila and maize genetics and introduced him to the classic genetic experiments of the 1930s performed by Lillian Morgan and Barbara McClintock. Haber's experiences teaching the course he had never taken, along with an intensive three-week yeast genetics course at Cold Spring Harbor Laboratory in 1970, sparked his career-long quest to elucidate genetic processes.
What he learned during that time established the foundation for a series of major contributions to the field. Over the course of his career Haber has made groundbreaking discoveries concerning the repair of DSBs, especially by developing methods to observe DNA repair in real time. He has demonstrated links between DNA repair and normal DNA replication and investigated how DNA-damaged cells resume mitosis after repair.
Today, Haber still appreciates the value of his obligatory undergraduate courses as learning experiences for himself, describing them as "forays into the 'beyond' [that] were instrumental in moving my research in new directions."