LSI Seminar Series: Kathleen Burns, M.D., Ph.D., Harvard Medical School and Dana-Farber Cancer Institute
A retrotransposon in cancer: The marker and the mutator
Eukaryotic genomes are replete with repetitive DNA attributable to the activity of self-propagating genetic sequences. In humans, this landscape is dominated by retrotransposons that make new copies of themselves by first being transcribed to RNA intermediates and then reverse transcribed to cDNA that is ultimately integrated into the genome.
Long interspersed element-1 (LINE-1)-encoded proteins are responsible for this process, which occurs both in the germline and in somatic tissues. Increased expression and animation of genomic LINE-1 sequences appear to be hallmarks of cancer and can be responsible for driving mutations in tumorigenesis. LINE-1 sequences encode a 6-kilobase (kb), bicistronic RNA intermediate transcribed from an internal RNA polymerase II promoter. The first of its open reading frames (ORFs) encodes ORF1 protein (ORF1p), which forms an RNA-binding homotrimer. The second ORF encodes ORF2p, which encompasses endonuclease and reverse transcriptase domains. These act in a coordinated manner to generate de novo genomic LINE-1 insertions, mutating cancer genomes.
Here, Burns will review data that ORF1 can serve as a marker of malignancies both in tissue biopsies and in the peripheral blood of cancer patients. She will also review published and preliminary data that L1-mediated mutagenesis generates frequent double stranded (ds)DNA breaks, leading to chromosomal deletions and inciting structural chromosomal instability (CIN). These findings suggest that LINE-1 may commonly contribute to cancer development and that enhancing its DNA damaging effects may represent a therapeutic strategy.
Speaker
Kathleen H. Burns is chair of the Department of Pathology at Dana-Farber Cancer Institute, vice chair of the Department of Pathology and senior hematopathologist at Brigham and Women’s Hospital, and a professor of pathology at Harvard Medical School. The Burns laboratory focuses on high copy number genomic repeats and transposable elements, their contributions to human disease, and ways to leverage this biology to better diagnose and treat cancers.
Burns is an elected member of the American Society for Clinical Investigation, the American Association of University Pathologists and the Interurban Clinical Club. Her honors include a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund, the Scriver Family Visiting Professorship in Genetic Medicine at McGill University, and the Daria Haust Lecturer of Pathology and Molecular Medicine at Queen’s University.
She received her M.D. and Ph.D. from Baylor College of Medicine and completed a clinical pathology residency and hematopathology fellowship at Johns Hopkins University School of Medicine, where she served as chief resident. Thereafter, she joined the faculty at Johns Hopkins, progressed through their academic ranks to professor with tenure, and served as the pathology department's deputy drector for research and programs and the medical school’s director of the physician scientist training program before being recruited to the Dana-Farber Cancer Institute.