Disruption of p53 cooperativity as a driver of cancer predisposition Renyta Moses

Format:

Book

Thesis/Dissertation

Author/Creator:

Moses, Renyta, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

Oncology.

Cellular biology.

Genetics.

Biology.

0992.

0379.

0369.

0306.

Local Subjects:

Oncology.

Cellular biology.

Genetics.

Biology.

0992.

0379.

0369.

0306.

Genre:

Academic theses

Physical Description:

1 online resource (129 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

p53 primarily acts as a transcription factor and binds to target sites on DNA cooperatively as a tetramer. This cooperative binding is mediated by salt-bridge interactions between p53 residues E180 and R181 from two different p53 monomers. Variants at the R181 residue are one of the most identified TP53 variants by germline genetic testing, however the mechanism by which these variants disrupt p53 tumor suppression is not understood. To investigate the clinical phenotype of p53 R181-variant carriers, I compared cancer incidence, type, and age of onset between families with R181H/C and families with other TP53 variants in three independent academic centers. To elucidate the mechanism of R181-mutant mediated tumorigenesis, I performed multi-omic and other functional analyses on CRISPR knock-in hemizygous R181H and R181C HCT116, MCF7, and LNCaP cancer cell lines compared to wild-type and knock-out controls. I show that families with TP53 pagesR181H and pagesR181C variants have an attenuated cancer risk phenotype compared to patients with hotspot loss of function TP53 variants. Despite this clinical phenotype, I find that p53 R181H and R181C variants have significantly diminished ability to transactivate p53 target genes. This loss of transactivation ability does not occur through defects in p53 structure or oligomerization, but through reduced cooperative binding to DNA. Despite the complete loss of p53's transcriptional function, I observe residual apoptotic activity in R181H and R181C mutant cells when treated with DNA-damaging agents. I show that the R181 variants retain transcription-independent apoptosis by localizing to the mitochondria and interacting with proapoptotic BAK to induce cytochrome c release and apoptosis. This dissertation reports the first separation of function DNA binding domain p53 mutation that results in retention of transcription-independent p53 functions despite loss of p53 transactivation activity, resulting in a reduced penetrance phenotype

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Maxwell, Kara N.; Murphy, Maureen E. Committee members: Feldser, David M.; Bernstein, Kara A.; Carroll, Martin P.; Baslan, Timour

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247979838

Access Restriction:

Restricted for use by site license