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RNA-Guided DNA Rearrangements in Breast Cancer

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Annual summary rept. 1 Mar 2010-30 Sep 2012

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Genome rearrangement and instability is a hallmark of cancer. In light of a previous study from our lab demonstrating RNA templated DNA rearrangements in Oxytricha, I searched for chimeric transcripts in normal human mammary cells to address the hypothesis that such chimeric RNAs may occasionally guide DNA rearrangements during breast tumorigenesis. By both computational and experimental analyses, I showed that even normal human cells produce chimeric RNAs, likely via RNA transsplicing without corresponding DNA rearrangement. The fact that rearrangements at the level of RNA can precede that of DNA suggests the possibility that the presence of chimeric RNA may predispose the DNA genome to rearrangements. In addition, I utilize the programmed genome remodeling in the ciliate Oxytricha as a model system to understand how a class of small RNAs called piRNAs facilitates genome-wide rearrangements. Through a combination of molecular, high-throughput sequencing, and synthetic biology approaches, I provide evidence for a model where piRNAs protect DNA against loss during Oxytricha genome rearrangement. This not only reveals a novel function for piRNAs, but also underscores a plasticity of RNAbased regulatory systems, because in two distantly-related ciliate species, small RNAs target DNA for deletion instead during genome reduction.

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  • Medicine and Medical Research

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