The Chromosome Stability Group (CSG) addresses factors that determine genome in/stability and chromosomal stress responses. The research extends across chromosomal challenges, cancer therapeutics, immunology and the impact of environmental agents. Using budding yeast model systems, the Group pursues two related areas of biology that deal with stresses to the genome. The first examines mechanisms of DNA damage, repair, mutations and genome changes in response to a variety of environmental agents and replication stresses and has extended findings to human cells and cancers. The second examines the human master regulator p53, a prominent tumor suppressor that is defective in most cancers and is central to toleration of a variety of stresses. Similar to genome stability studies, many of the findings in human cells are driven by finding with human p53 expressed in yeast.
DNA double-strand breaks (DSBs) and single-strand intermediates in repair. DSBs are major sources of genetic change in humans, both good and bad, and can result from environmental damage as well as programmed events. The CSG has pursued extensively genetic controls and mechanisms of DSB repair. While DSBs are efficiently repaired, the CSG established that most gross chromosomal arrangements induced by ionizing radiation in yeast are due to DSBs in repeated DNAs that can "reshape the genome." The components that bind sister chromatids together, cohesin, are limiting and prevent inappropriate repair. Reduction in cohesin opens the genome to recombination between homologous sequences and genome instability. The CSG found that DSBs can arise through processed events between closely-spaced single strand lesions. A novel system based on breakage of a circular chromosomes allowed investigation of one of the earliest steps in processing and repair of random DSBs--resection to generate single strand tails-- and has been used to reveal coordination of repair between DSB ends. A similar system based on circular EBV has been developed in human cells to address DSBs, single strand breaks, repair and inhibitors.
Damage-induced localized hypermutability and relation to cancer. The CSG established that environmental agents such as UV and alkylating chemicals can increase mutation frequencies over 1000-fold in long (10-20 kb) single-strand regions occasionally formed in genomes at uncapped telomeres or uncoupled replication forks and during early steps in DSB repair. Because the lesions are not subject to repair, they result in mutations that frequently appear as clusters. Mutation clusters are proposed to be an important source of genomic alteration, thereby contributing to genetic disease, carcinogenesis and adaptive evolutionary changes, and yeast systems have been developed to better assess mutational susceptibility of ssDNA in response to various environmental agents. Based on the mutation clusters discovered in yeast, the DNA sequences from human tumors were examined and nearly half had clusters. However, they were generally ascribed to APOBEC cytosine deaminases that contribute to human immunity and natural defenses against viruses and can damage single strand DNA. These unexpected findings suggest novel sources of cancer development. (Also see website of Dr. Dmitry Gordenin, a member of the CSG)
DNA replication and genome instability. The act of DNA replication must be highly coordinated and accurate. The CSG has identified many DNA motifs (e.g., inverted repeats), environmental factors (e.g., cadmium) and genetic defects that put replicating DNA at risk for mutation and breakage. Recent efforts address lagging strand replication where millions of Okazaki fragments must be joined to prevent subsequent DSBs. The exceptional accuracy was found to require coupled biochemical activities of two nucleases centered around DNA Pol delta strand-displacement synthesis. (Also see Dr. Dmitry Gordenin, website).
The p53 master regulatory network. The p53 tumor suppressor is a major regulator of DNA repair and damage checkpoints in humans. Using systems developed in yeast and human cells to address functionality of p53 target sequences and p53 cancer mutants, the CSG has revealed a greatly expanded universe of p53 targets, including noncanonical sequences, human diversity in the network as well as variations in responses to specific stresses such as UV and anticancer agents. In addition, p53 can cooperate in cis with estrogen receptor to enhance responsiveness of normal and mutant p53s. The CSG established new roles for p53 in immunity and inflammation finding unique p53-NFkappaB interactions in human macrophages and showing that the innate immunity Toll-like receptor (TLR) gene family in primary human cells and many cancer lines responds to chromosome stressors, mostly via p53. Interestingly, the DNA metabolism and TLR groups of genes have acquired p53 responsiveness late in evolution. (Also see website of Dr. Daniel Menendez, a member of the CSG)
Dr. Resnick's work focuses on mechanisms of genome stability and on the function of the p53 master regulatory network that signals stress and DNA chromosomal damage using both yeast and human cells. He received his Ph.D. in Biophysics from U. California, Berkeley. Following faculty positions at U. Rochester and Medical Research Council (MRC), London, England, he moved in 1979 to the NIEHS in Research Triangle Park, NC. He is Head of the Chromosome Stability Section in the Laboratory of Molecular Genetics and is an Adjunct Professor at Duke University and U. North Carolina, Chapel Hill. Dr. Resnick was named NIEHS Scientist of the Year in 2008 and has had several "Paper of the Year" awards. He was elected a Fellow in the American Association for the Advancement of Science in 2012 for his work on the mechanisms of recombination following DNA damage. He has co-organized several meetings relating to p53 function and mutants. He has authored over 200 papers and holds 7 patents.