{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/363866"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/363866","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Functionality of mutant p53 in early tumorigenesis","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Sheekey, Eleanor"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Narita, Masashi"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-09-29","date_published":"2023-09-29","updated_at":"2026-07-22T22:24:20Z","subjects":["aging","ATAC-seq","cancer","cell competition","cell fitness","cellular senescence","ChIP-seq","chromatin","DNA damage","dominant negative","gain of function","p53","senescence","STAT1"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/05d06d34-5617-4ff7-8567-9f2050a004f9/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["000000021501550X"],"render_values":[{"text":"0000-0002-1501-550X","href":"https://orcid.org/0000-0002-1501-550X","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.105755","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Narita, Masashi"]},{"key":"dc:creator","label":"Author","values":["Sheekey, Eleanor"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["000000021501550X"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2023-09-29"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/363866"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["aging","ATAC-seq","cancer","cell competition","cell fitness","cellular senescence","ChIP-seq","chromatin","DNA damage","dominant negative","gain of function","p53","senescence","STAT1"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/05d06d34-5617-4ff7-8567-9f2050a004f9/download","https://www.rioxx.net/licenses/all-rights-reserved/"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2030-02-07"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.105755"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/1b7076a4-e98d-4d0a-b3be-153db0af19f8/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["TP53, encoding a stress-activated transcription factor, is commonly mutated in human cancers. 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