Abstract
Abstract Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number, yet we know virtually nothing about what governs its copy number, stability, and sequence. Ribosomal DNA is present in many tandem repeats that are incredibly important because 1) they encode the template for the RNA component of ribosomes, 2) they organize large parts of nearly every human chromosome and 3) they can titrate factors involved in chromosomal processes, with profound impact on DNA replication, repair, and gene expression. We applied computational and droplet digital PCR approaches to explore rDNA copy number in normal and cancer states in human and mouse genomes. We find that the copy number is similar between tissues from the same mouse, and is similar within inbred mouse strains, but can vary widely between individuals in an outbred strain. PTEN is a tumor suppressor and negative regulator of mTOR activity that is critical for genome stability. We find that hematopoietic stem cells from a PTEN-/- mouse model for leukemia have lower rDNA copy number than normal tissue, associated with hypersensitivity to DNA damage. Remarkably, analysis of three human cancer genome projects reveals low rDNA copy number relative to matched normal tissue. Our analysis reveals a genomic signature associated with hyperactive mTOR in osteosarcoma that includes loss of rDNA copies accompanied by an increase in sequence heterogeneity, as well as additional genes that co-vary in copy number. PTEN-mTOR may normally contribute to maintenance of ribosomal DNA. This abstract is also being presented as Poster A38. Citation Format: Baoshan Xu, Hua Li, John Perry, Bethany Harris, Brian Slaughter, Jay Unruh, Vijay Pratap Singh, Musinu Zakari, William McDowell, Linheng Li, Jennifer L. Gerton. PTEN-mTOR pathway serves as a guardian of ribosomal DNA. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR06.
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