Scientific Director, Cancer Biology Research Program
Associate Professor, Cancer Biology - GIDP
Associate Professor, Genetics - GIDP
Chair, ABBS Program
Genomic Instability and Cancer Susceptibility
Dr. Ellis’ career has been devoted to understanding the functional consequences of genetic variation in humans. He has worked in the human molecular genetics of X chromosome inactivation and Y chromosome-mediated sex determination, evolution and population genetics of human sex chromosomes, the molecular genetics of genomic instability and DNA repair. The current research focus of the laboratory is the relationship between genomic instability and cancer susceptibility. We are interested in both high-penetrance and low-penetrance cancer susceptibility alleles, the population genetics of the susceptibility alleles, and molecular mechanisms linking the alleles with disease susceptibility and carcinogenesis. The laboratory investigates two major areas:
Regulation of Homologous Recombination in Human Cells
Cells contain numerous DNA repair systems that maintain the integrity of the genome. When a component of one of these systems is mutated, either somatically or in the germline, cells accumulate mutations and susceptibility to cancer increases. Homologous recombination (HR) is a high-fidelity pathway that can restart broken replication forks and repair DNA double-strand breaks. HR is carefully controlled so that it is called into play only when it is needed. In the autosomal recessive disorder Bloom's syndrome (BS), there is excess HR.
The gene mutated in BS is BLM. BLM is a DNA helicase of the RecQ family, and it plays a critical role in controlling excessive HR. We study the regulation of BLM’s function in HR. BLM is regulated by post-translational protein modification by SUMO (small ubiquitin-like modifier). For multiple HR proteins, SUMO acts to promote HR. For BLM, SUMOylation acts as a switch to promote BLM’s pro-recombinogenic roles in HR at the same time as inhibiting its anti-recominbogenic roles. We are investigating the mechanisms by which SUMO modification of BLM and other proteins regulates HR and DNA damage responses.
Genetic analysis of colorectal cancer susceptibility
Genetic risk factors play an important role in the development of colorectal cancer (CRC). Hereditary CRC syndromes have demonstrated the importance of DNA repair in CRC susceptibility, and many of the environmental factors that increase the risk of CRC development do so by causing increased DNA damage. While DNA damage and repair are clearly important, genetic factors that influence cell proliferation in the gut epithelium also can increase CRC risk. Our overall goals are (1) to identify clinically useful genetic risk factors that predict a person’s risk of developing CRC, (2) to elucidate the role these genetic risk factors play in disease pathogenesis, and (3) to develop predictive models that take into account both genetic and environmental factors in determining CRC risk.
To address these goals, we are conducting multiple genomics analyses (including genome-wide association studies, exome and copy number analyses of CRCs, expression array and expression candidate trait locus analyses) to identify and characterize cancer genes. An area of special interest is comparative genomics research, leveraging differences in cancer epidemiology and genetics in African Americans and whites. Because the African American population is much more genetically diverse than populations derived from Europe, these comparative studies can better localize shared susceptibility alleles and identify novel population-specific alleles. The studies also shed light on the causes of health disparities in this population.