{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/316345"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/316345","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Terminal uridyl transferases: TUT4/7-mediated RNA metabolism in cancer","abstract":"Nascent RNA is subjected to a wide range of RNA metabolic processes such as non-templated additions of uridines at the 3′ end after it has been transcribed. These additions are catalysed by the terminal uridyl transferases TUT4 and TUT7 (TUT4/7). Defects in TUT4/7-mediated functions result in sterility, failed embryogenesis and susceptibility to viral pathogens. Additionally, TUT4/7 have been shown to be key regulators of the tumorigenic LIN28A/let-7 pathway. However, a full understanding of TUT4/7-mediated mechanisms of RNA control that impinge on tumorigenesis is still missing. In this thesis, I establish catalytic knockouts of TUT4/7 in two distinct cancer cell types to understand the mechanistic aspects of TUT4/7-mediated regulation in tumorigenesis. I observe cell type specific defects in cancer properties in the TUT4/7 double mutants. As the cell type specific differences in defects could be due to the presence or absence of LIN28A, I integrated the LIN28A cDNA in the LIN28A-negative cancer cell line. This allowed the comparison of TUT4/7-dependent gene expression changes in a LIN28A context. My findings suggest that miRNAs and mRNAs do not generally depend on LIN28A-mediated TUT4/7 regulation. Instead, I find that TUT4/7 can shape the transcriptomic landscape according to the cancer cell type independently of LIN28A. Furthermore, I provide new examples of emerging compensatory mechanisms that arise upon TUT4/7 loss. I observe that loss of uridylation results in a simultaneous gain in 3′ adenylation. The extent of gain in adenylation is miRNA-specific with some miRNAs overexpressing adenylated isomiRs upon TUT4/7 loss. This might contribute to the observed proliferative defects in the TUT4/7 double mutants. Finally, I show that TUT4 and TUT7 have non-redundant functions. I identify miRNA targets of TUT7 that are not uridylated by TUT4 and vice versa. I also present ongoing work on the development of an effective technique to identify direct targets of TUT4/7 and to gain a comprehensive view of RNA control mechanisms based on sequence specific features. Having examined the TUT4/7-mediated regulatory networks at a transcriptome level, my findings show that TUT4/7 is a promising cancer target for an ovarian cancer subtype. However, exploring the biological effects of the novel compensatory mechanisms that emerge upon TUT4/7 loss warrant further study so as to prevent deleterious consequences when targeting TUT4/7 as a potential cancer therapy.","abstract_html":"Nascent RNA is subjected to a wide range of RNA metabolic processes such as non-templated additions of uridines at the 3′ end after it has been transcribed. These additions are catalysed by the terminal uridyl transferases TUT4 and TUT7 (TUT4/7). Defects in TUT4/7-mediated functions result in sterility, failed embryogenesis and susceptibility to viral pathogens. Additionally, TUT4/7 have been shown to be key regulators of the tumorigenic LIN28A/let-7 pathway. However, a full understanding of TUT4/7-mediated mechanisms of RNA control that impinge on tumorigenesis is still missing. In this thesis, I establish catalytic knockouts of TUT4/7 in two distinct cancer cell types to understand the mechanistic aspects of TUT4/7-mediated regulation in tumorigenesis. I observe cell type specific defects in cancer properties in the TUT4/7 double mutants. As the cell type specific differences in defects could be due to the presence or absence of LIN28A, I integrated the LIN28A cDNA in the LIN28A-negative cancer cell line. This allowed the comparison of TUT4/7-dependent gene expression changes in a LIN28A context. My findings suggest that miRNAs and mRNAs do not generally depend on LIN28A-mediated TUT4/7 regulation. Instead, I find that TUT4/7 can shape the transcriptomic landscape according to the cancer cell type independently of LIN28A. Furthermore, I provide new examples of emerging compensatory mechanisms that arise upon TUT4/7 loss. I observe that loss of uridylation results in a simultaneous gain in 3′ adenylation. The extent of gain in adenylation is miRNA-specific with some miRNAs overexpressing adenylated isomiRs upon TUT4/7 loss. This might contribute to the observed proliferative defects in the TUT4/7 double mutants. Finally, I show that TUT4 and TUT7 have non-redundant functions. I identify miRNA targets of TUT7 that are not uridylated by TUT4 and vice versa. I also present ongoing work on the development of an effective technique to identify direct targets of TUT4/7 and to gain a comprehensive view of RNA control mechanisms based on sequence specific features. Having examined the TUT4/7-mediated regulatory networks at a transcriptome level, my findings show that TUT4/7 is a promising cancer target for an ovarian cancer subtype. However, exploring the biological effects of the novel compensatory mechanisms that emerge upon TUT4/7 loss warrant further study so as to prevent deleterious consequences when targeting TUT4/7 as a potential cancer therapy.","abstract_has_math":false,"creators":["Medhi, Ragini"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Miska, Eric"],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-09-01","date_published":"2020-09-01","updated_at":"2026-07-22T22:24:11Z","subjects":["Cancer","Tumorigenesis","RNA","RNA metabolism"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d0cddbfe-7946-4a3c-9b17-2b1dc085cb4e/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000227800708","000000024450576X"],"render_values":[{"text":"0000-0002-2780-0708","href":"https://orcid.org/0000-0002-2780-0708","code":true},{"text":"0000-0002-4450-576X","href":"https://orcid.org/0000-0002-4450-576X","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.63455","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Miska, Eric"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Storm Therapeutics Ltd."]},{"key":"dc:creator","label":"Author","values":["Medhi, Ragini"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000227800708","000000024450576X"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2020-09-01"]},{"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/1810/316345"]},{"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":["Cancer","Tumorigenesis","RNA","RNA metabolism"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d0cddbfe-7946-4a3c-9b17-2b1dc085cb4e/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.63455"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a94e2999-cb2c-445b-a897-35a25fd6f53e/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Nascent RNA is subjected to a wide range of RNA metabolic processes such as non-templated additions of uridines at the 3′ end after it has been transcribed. 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My findings suggest that miRNAs and mRNAs do not generally depend on LIN28A-mediated TUT4/7 regulation. Instead, I find that TUT4/7 can shape the transcriptomic landscape according to the cancer cell type independently of LIN28A. Furthermore, I provide new examples of emerging compensatory mechanisms that arise upon TUT4/7 loss. I observe that loss of uridylation results in a simultaneous gain in 3′ adenylation. The extent of gain in adenylation is miRNA-specific with some miRNAs overexpressing adenylated isomiRs upon TUT4/7 loss. This might contribute to the observed proliferative defects in the TUT4/7 double mutants. Finally, I show that TUT4 and TUT7 have non-redundant functions. I identify miRNA targets of TUT7 that are not uridylated by TUT4 and vice versa. I also present ongoing work on the development of an effective technique to identify direct targets of TUT4/7 and to gain a comprehensive view of RNA control mechanisms based on sequence specific features. Having examined the TUT4/7-mediated regulatory networks at a transcriptome level, my findings show that TUT4/7 is a promising cancer target for an ovarian cancer subtype. 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My findings suggest that miRNAs and mRNAs do not generally depend on LIN28A-mediated TUT4/7 regulation. Instead, I find that TUT4/7 can shape the transcriptomic landscape according to the cancer cell type independently of LIN28A. Furthermore, I provide new examples of emerging compensatory mechanisms that arise upon TUT4/7 loss. I observe that loss of uridylation results in a simultaneous gain in 3′ adenylation. The extent of gain in adenylation is miRNA-specific with some miRNAs overexpressing adenylated isomiRs upon TUT4/7 loss. This might contribute to the observed proliferative defects in the TUT4/7 double mutants. Finally, I show that TUT4 and TUT7 have non-redundant functions. I identify miRNA targets of TUT7 that are not uridylated by TUT4 and vice versa. I also present ongoing work on the development of an effective technique to identify direct targets of TUT4/7 and to gain a comprehensive view of RNA control mechanisms based on sequence specific features. Having examined the TUT4/7-mediated regulatory networks at a transcriptome level, my findings show that TUT4/7 is a promising cancer target for an ovarian cancer subtype. However, exploring the biological effects of the novel compensatory mechanisms that emerge upon TUT4/7 loss warrant further study so as to prevent deleterious consequences when targeting TUT4/7 as a potential cancer therapy."],"dc:format.checksum.md5":["4616c14a1edb525f3922f5cf90ccce6f","353adac0d1ebdfd65ab16480263c3c87"],"dc:identifier.doi":["10.17863/CAM.63455"],"dc:identifier.uri":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a94e2999-cb2c-445b-a897-35a25fd6f53e/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/316345"],"dc:rights":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d0cddbfe-7946-4a3c-9b17-2b1dc085cb4e/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"dc:subject":["Cancer","Tumorigenesis","RNA","RNA metabolism"],"dc:title":["Terminal uridyl transferases: TUT4/7-mediated RNA metabolism in cancer"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:24:11Z"}