Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Andre Nussenzweig

Abstract

Studies of genome integrity have been historically limited to low-resolution tools that afford little-to-no information on precise genomic locations of DNA damage. Because many sources of genomic instability begin with endogenous DNA breaks at specific genetic sequences, it is possible to develop new, next-generation sequencing approaches to understand classic cytological observations in the field of DNA repair. I have employed here protocols to map DNA breaks (END-seq) and nascent DNA synthesis (EdU-seq) to address mechanisms of genomic instability during both meiosis and mitosis. Cell division presents unique challenges to genome integrity. During meiosis, the enzyme SPO11 generates intentional, requisite DNA breaks to initiate meiotic recombination and homologous chromosome synapsis. In contrast, DNA damage during mitosis is primarily used to prevent deleterious outcomes that have been implicated in cancer and age-related pathologies. I have utilized and modified next-gen technologies to address numerous unanswered mechanisms of fragility and repair during both meiosis and mitosis. While it is common to think of DNA repair as evolved processes that combat environment-derived damage, these studies in cell division, a process that relies on inducing and repairing damage, illustrate a different evolutionary perspective in which damage and repair are also controlled pathways to maintain and adapt genomes across the tree of life.

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