Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Kristina H. Schmidt, Ph.D.

Committee Member

Huzefa Dungrawala, Ph.D.

Committee Member

Marcus Cooke, Ph.D.

Committee Member

Alvaro Monteiro, Ph.D.

Keywords

RecQ, Oxidative stress, DNA damage, Homologous Recombination, Replication stress, Condensin, SMC2

Abstract

Bloom syndrome (BS) is an extremely rare autosomal recessive genetic disorder caused by defects in the BLM gene. Patients with BS display a broad phenotypic spectrum including abnormally short stature, microcephaly, sun sensitivity, insulin resistance, perpetual oxidative stress, and a ~300-fold greater propensity for developing cancer than the general population. As such, BS patients typically do not live past their 20’s. The BLM gene encodes the BLM helicase, a member of the highly conserved RecQ family of 3’ to 5’ DNA helicases. Most of our cellular understanding of BLM is through its role in DNA damage repair through the homologous recombination repair pathway; however, little has been investigated into the roles of BLM in unperturbed cells and how these may contribute to the pleiotropic characteristics of Bloom syndrome. Here, we demonstrate a novel role of BLM in regulating mitochondrial homeostasis and identify a new interaction between BLM and the condensin II protein complex in unperturbed interphase. The novel interaction we identify between BLM and the condensin II complex is important for both replication and DNA repair-associated processes to maintain genome integrity. We show that BLM loss is also associated with a dysfunction in mitochondrial fission/fusion dynamics, which is accompanied by unscheduled cyclin B1 expression in G1 phase mitochondria. Together, these studies demonstrate the multiple mechanistic roles of BLM in unperturbed cells, whose failures may contribute to the pathogenicity of BS.

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