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The elucidation of MCM10's role in human disease

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The elucidation of MCM10's role in human disease

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2022-11

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DNA replication is a ubiquitous process in the formation of every cell in the human body. Given the size of the human genome, there are many origins of replication to complete its duplication in a timely manner. At each of these replication origins, the coordination of multiple proteins needs to be orchestrated for efficient DNA replication. The process of DNA replication can be broken down into distinct steps including origin licensing, origin firing, DNA elongation and termination. This thesis focuses on minichromosome maintenance protein 10 (MCM10) which is an essential replication protein with roles in both origin firing and elongation. Without MCM10 the replicative helicase cannot be activated to unwind parental DNA to allow for the synthesis of daughter strands. Additionally, MCM10 recruits polymerase alpha (polα) which is important for synthesis initiation on both the leading and lagging strands. MCM10 travels with the replication fork. During DNA elongation, MCM10 continues to coordinate polα recruitment for lagging strand synthesis. Additionally, MCM10 plays a role in stabilizing replication forks in the presence of replication stress. Although cancer is likely the disease most often associated with impaired DNA replication, several congenital diseases arise due to defects in DNA replication genes. One of these diseases is natural killer (NK) cell deficiency (NKD). NK cells are lymphocytes of the innate immune system and are critical to prevent viral infection. We have recently reported that mutations in MCM10 can cause NKD and other immune dysfunction depending on the severity of the mutation. In this thesis, I explore the impact of MCM10 deficiency on genomic instability in multiple model cell lines as well as NK cell differentiation. I find that MCM10 is haploinsufficient and causes genomic instability including telomere erosion. This telomere erosion is also seen as MCM10 heterozygous cells progress through NK cell differentiation and contributes to the inability of MCM10 heterozygous cells to generate mature NK cells. Based on these results, I hypothesize that telomere erosion is a tissue-specific hallmark of MCM10 deficiency that triggers premature senescence in certain cell lineages. Surprisingly, not all congenital diseases caused by defects in DNA replication result in NKD or even a broader hematopoietic defect. In fact, the disease phenotypes seem to segregate around a protein’s role in origin licensing, origin firing, or DNA elongation. By exploring the underlying mechanism of MCM10 associated disease, this thesis begins to explore why tissue specificity arises in DNA replication defects.

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University of Minnesota Ph.D. dissertation. November 2022. Major: Biochemistry, Molecular Bio, and Biophysics. Advisor: Anja Bielinsky. 1 computer file (PDF); xiii, 137 pages.

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Schmit, Megan. (2022). The elucidation of MCM10's role in human disease. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/260143.

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