Graduation Year

2019

Document Type

Thesis

Degree

M.S.

Degree Name

Master of Science (M.S.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Younghoon Kee, Ph.D.

Committee Member

Meera Nanjundan, Ph.D.

Committee Member

Margaret Park, Ph.D.

Keywords

Cell Cycle, LYRIC, OTUD6B, p21

Abstract

The posttranslational modification ubiquitination is major regulatory mechanism used throughout cell signaling pathways such as cell cycle regulation and the DNA damage response. As such, the E3 ligases and their deubiquitinating enzyme counterparts, which conjugate and deconjugate ubiquitin to and from protein substrates respectively, must be tightly regulated to prevent aberrant cellular behaviors that could lead to diseases such as cancer.

Of the five families of deubiquitinating enzymes, the Ovarian Tumor Domain (OTU) family is fairly unique and under-studied; many of its family members hold a linkage specificity to certain ubiquitin chains and a number of them have been implicated in the DNA damage response and innate immune signaling. Among the understudied isopeptidases within this family, the Ovarian Tumor Domain Deubiquitinating enzyme 6B (OTUD6B), has remained functionally ambiguous and its binding partners are unconfirmed. Studies suggest OTUD6B may be involved in translational regulation, cell growth, or be vital for 26S proteasomal formation; it is currently undecided if OTUD6B function is vital development, cellular growth, and proliferation or if it is an inhibitor of such events.

In the following work, we bring clarity to this dispute by showing that decreased OTUD6B induces p21 protein level increase, cellular senescence, and decreased cell growth and migration rates, suggesting OTUD6B functions is a promoter of cell proliferation. We also provide evidence that OTUD6B is a binding partner of the Lysine-rich CEACAM-1-associated protein (LYRIC), an oncogene implicated in promoting metastasis in various cancers. Such findings highlight a potentially new, cancer promoting, pathway involving the regulation of p21 and LYRIC protein levels, as well as adds transparency into the contradicting results observed within OTUD6B published literature. Such new understanding of OTUD6B functional properties may bring insight to the field of ubiquitin dependent regulation mechanisms and possibly position OTUD6B as a new therapeutic target against cancers.

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