Functionality of mutant p53 in early tumorigenesis

TP53, encoding a stress-activated transcription factor, is commonly mutated in human cancers. Most of these mutations are missense mutations which, in the presence of WT-p53 (p53mut/+), can cause loss of function (LOF), dominant-negative (DN) and/or gain of function (GOF) activities. However, mutant p53 is more commonly studied following loss-of-heterozygosity (p53mut/-) which is thought to promote tumorigenesis. The functionality of mutant-p53 in early tumorigenesis (p53mut/+) has been underexplored but it may uncover how the mutation primes a cell for aberrant activities. By modelling the heterozygous expression of p53R175H in unstressed, acute- and chronic-stress conditions (DNA damage induced senescence, DDIS), I have identified potential DN and GOF activities and the underlying molecular mechanism using the latest -omics and chromatin binding assays. Despite the DN activity being strong and p53R175H-dose-dependent in acute stress, the cells show a stress-dependent cell fitness response, with the chronic stress state making the heterozygous p53R175H less fit than WT-cells.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Sheekey, Eleanor

Advisor dc:contributor.advisor

• Narita, Masashi

• aging
• ATAC-seq
• cancer
• cell competition
• cell fitness
• cellular senescence
• ChIP-seq
• chromatin
• DNA damage
• dominant negative
• gain of function
• p53
• senescence
• STAT1

Licence

• https://www.repository.cam.ac.uk/bitstreams/05d06d34-5617-4ff7-8567-9f2050a004f9/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-1501-550X

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/363866