Award Date

5-15-2026

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

First Committee Member

Hui Zhang

Second Committee Member

Hong Sun

Third Committee Member

Gary Kleiger

Fourth Committee Member

Edwin Oh

Number of Pages

172

Abstract

The SRY (Sex-determining Region Y) protein is a transcription factor encoded on the Y chromosome and is the key regulator responsible for initiating male sex determination in mammals. During early embryonic development, SRY activates the genetic program that leads to testis formation by promoting the expression of downstream genes involved in male gonadal differentiation. Mutations or dysregulation of SRY can lead to disorders of sex development such as male-to-female sex conversion and hermaphroditism, highlighting its critical role in sex determination.

SRY belongs to the SOX (SRY-related HMG-box) family of transcription factors, which includes the proteins SOX1, SOX2 and SOX3. These proteins share a highly conserved highmobility group (HMG) DNA-binding domain, which allows them to bind and bend DNA to regulate transcription. Functionally, SOX1, SOX2 and SOX3 play major roles in embryonic development and cell fate determination, particularly in the maintenance and differentiation of neural progenitor cells. SOX2 is especially known for its role in maintaining pluripotency and self-renewal in embryonic stem cells, whereas SOX1 and SOX3 are primarily involved in neural development and central nervous system formation. SOX2 amplification was found to be closely related to many cancers, including lung, esophagus, and oral cavity, and small cell lung carcinomas and glioblastoma multiforme. SOX2 is over-expressed in many poorly differentiated and aggressive cancers, including breast, ovarian, gastric, and colon carcinomas. Mutations or dysregulation of the SOX1 protein cause neurodevelopmental disorders and epilepsy, and mutations or deletions of the SOX3 protein causes X-linked hypopituitarism and intellectual disabilities due to impaired neural and pituitary development.

SRY and SOX1-3 proteins contain a conserved motif that is methylated by the SET7 methyltransferase and demethylated by LSD1, lysine-specific histone demethylase 1A. siRNAmediated knockdown of human LSD1 protein and mouse Lsd1 knockouts destabilized the human and mouse SOX1-3 proteins and human SRY protein indicating that LSD1 is crucial to maintain the stability of the SOX family proteins. Methylated lysine residues of the SOX family proteins are bound by the methyl-binding protein L3MBTL3, and they are targeted for proteolytic degradation via the proteasome. Loss of L3MBTL3 in human cells that are deficient in LSD1 and mouse L3mbtl3 knockouts re-stabilized the target substrates suggesting that L3MBTL3 is required for the degradation of the SOX family proteins. DCAF5 is a substrate specific receptor of the CRL4 E3 ubiquitin ligase complex that polyubiquitinates substrates and targets them for degradation. Silencing DCAF5 in human cancer cells lacking LSD1, and homozygous deletion of Dcaf5 in mice caused the stabilization of the SOX family proteins. These in vitro and in vivo assays for SRY and SOX1-3 proteins showed that the stability of these proteins are dynamically regulated in a methylation-dependent manner. We are proposing a methylation-dependent regulatory pathway that control the stability of these critical proteins for maintaining cellular identity and functional integrity.

Keywords

Methylation; Protein regulation; Protein stability; SOX2; SRY

Disciplines

Chemistry | Genetics and Genomics | Life Sciences

File Format

PDF

File Size

23500 KB

Degree Grantor

University of Nevada, Las Vegas

Language

English

Rights

IN COPYRIGHT. For more information about this rights statement, please visit http://rightsstatements.org/vocab/InC/1.0/

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