Author ORCID Identifier

0000-0003-3836-1808

Date of Graduation

8-2021

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Bin Wang

Committee Member

Pierre McCrea

Committee Member

Richard Behringer

Committee Member

Kevin McBride

Committee Member

Zhiqiang Zhang

Abstract

Genomic instability can be induced by various forms of genotoxic stress and it is a hallmark of human cancer that is associated with metastasis, therapeutic resistance, and poor prognosis. During replication stress, the replication fork stalls and forms a reversed fork which may be degraded by several DNA nucleases. At the stalled fork, genome stability is maintained by fork end protection and subsequent restart of the replication. Abro1 has been shown to play an important role in protecting the integrity of the stalled replication forks by inhibiting DNA2 nuclease. Deficiency of Abro1 leads to stalled replication fork degradation and genomic instability. Moreover, Abro1-null mice show signs of inflammatory response such as enlarged spleens, increased numbers of T cells and B cells, elevated levels of IL6 and TNF-alpha in the blood, and increased immune cell infiltration in major organs. Recently, it has been shown that genomic instability can trigger cGAS/STING pathway , inducing activation of the innate immune response and inflammatory gene expression through cGAS binding to cytoplasmic DNA or localizing to micronuclei in response to DNA damage. Here, I found that replication stress induced by Abro1 deficiency leads to ssDNA accumulation in the cytoplasm triggering activation of the cGAS/STING pathway with upregulation of inflammatory genes and increase of the secretion of chemokines, which direct the migration of immune cells. My results suggest possibilities to modulate the host immune system response and ultimately the success of immune checkpoint blockade therapies.

Keywords

Innate Immune Response, Replication Stress, Fork Protection Defect, Abro1

Available for download on Tuesday, August 09, 2022

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