Multifaceted regulation of the DNA repair machinery and suppression of aberrant transcription by telomere proteins

At the ends of chromosomes, structures known as telomeres play an important role in protecting the integrity of genetic information contained in DNA. Telomeres can be likened to aglets, the caps at the tips of shoelaces; when the aglets are missing, the shoelaces (chromosomes) get frayed and fall apart. Many proteins work together to protect telomere DNA, and defects in these proteins can lead to chromosome destabilization. This study will provide insights into abnormal transactions at telomeres and improve understanding of how genetic information is protected. This project will also provide opportunities for training many community college students in the technical and critical thinking skills necessary for future scientific careers, and therefore have broadly beneficial impacts on society. Telomeres are specialized nucleoprotein structures that allow cells to distinguish normal chromosome ends from double strand breaks. When these structures are defective, telomere DNA becomes deprotected and is subjected to abnormal “repair” reactions, which can include degradation, recombination, and end-to-end fusion. Our understanding of the factors that mediate and regulate abnormal telomere repair is incomplete. For example, abnormal telomeres are often transcribed at high levels, and both the mechanisms of transcription and the functional significance of the transcripts are poorly understood. This study will address two major questions. First, how are abnormal telomere repair pathways regulated by the cell cycle? Second, what factors are involved in abnormal telomere transcription and how do the transcripts impact abnormal telomere repair? The project will combine biochemical and molecular genetic approaches to address these questions in the fungus Ustilago maydis (a maize pathogen) that has well-developed genetic tools and significant similarities to animal cells with respect to telomere regulation. The outcomes will advance our understanding of mechanisms that underlie abnormal repair reactions at deprotected telomeres. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.