From the time that we begin as a fertilized egg to having a body of 50 trillion cells, the DNA sequences of our chromosomes remain incredibly stable. This general problem, known as “genome stability,” helps to promote health over the lifespan. In contrast, in diseases like cancer, cells exhibit very high levels of genome instability. Dr. James Haber, Professor of Biology and Director of the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, uses yeast cells as a model organism to understand how cells accurately repair their broken chromosomes, but also what happens if these front-line repair processes fail. By studying yeast cells, where the both accurate and less precise repair mechanisms can be studied in much greater detail than in human cells, he and his team are identifying key steps in the process. It is then possible to evaluate human cells to find out how normal cells preserve chromosome integrity and what safeguards are lost in precancerous cells. Therefore, Dr. Haber’s fundamental research and development of sophisticated tools is advancing science towards an understanding of how cells preserve chromosomes integrity and furthermore to provide models that can be implemented to prevent disease.

Dr. Haber’s work is notable for the development of novel genetic and molecular biology assays to understand how DNA damage is repaired in living cells. The cell lines he has developed have been provided with no strings to more than 100 labs around the world. In fact, his collaborations with over 50 other labs during his career in addition to close mentorship of his talented undergraduate students, graduate students, and postdocs, have continually provided insights that have led to advances in understanding and treating human disease. Awarded the Genetic Society of America’s Thomas Hunt Morgan medal for lifetime achievement in genetics, and elected as a member of the US National Academy of Sciences and the American Academy of Arts and Sciences, Dr. Haber is at the forefront of analyzing the way defined chromosome breaks are sensed and repaired, in unprecedented detail.

Current research includes:

• DNA Damage: Model organisms and humans respond to DNA damage in almost identical ways by triggering a signaling cascade known as the DNA damage checkpoint. When a protein recognizes that there is a broken chromosome, a signal is propagated that tells the cell not to divide. Dr. Haber is interested in understanding how such signaling is turned on, but especially, how these alarms are maintained but then turned off if the damage is repaired. He and his team have created new cell lines in which key kinase proteins can be quickly inactivated after the damage signal has been turned on, in order to learn which of these proteins are needed to sustain the signal and eventually to turn it off.  

• Detecting Protein Modifications: Dr. Haber’s lab has discovered that mutations of specific sites in a key signaling protein called ATR creates a situation in which the cascade turns on normally but then cannot be turned off. However, when the sites were changed to mimic a normal modification produced by the ATR protein itself, the signal cascade turned off rapidly. These behaviors suggest that two sites in the ATR gene are the key to regulating the activity of this essential protein kinase. To prove that these sites are important regulators, Dr. Haber and his team are developing immunological approaches to detect these modifications.

• Uncovering Key Genes: DNA damage provokes cells to degrade proteins that would otherwise propel the cells into mitosis. Restraining cell division allows time for the cell to repair the damage. There are two degradation processes, proteasomal degradation and autophagy. Dr. Haber’s lab has identified genes that are specifically important in turning on the autophagy response after creation of an unrepaired chromosome break. He now hopes to study which nuclear positions are transported to the vacuole for degradation by autophagy after DNA damage is inflicted. It is already clear that human cells respond in similar ways to damage by triggering these same pathways of protein degradation. By uncovering new genes essential for this process in yeast , Dr. Haber hopes to uncover the human versions of these genes and to promote the study of how these genes protect human cells from disease.