{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/90688"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/90688","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Enzymatic synthesis of defined-length poly(ADP-ribose) and the investigation of cell-permeable poly(ADP-ribose) glycohydrolase inhibitors","abstract":"Poly(ADP-ribosylation) (PARylation) is an important post-translational modification that maintains genomic stability in a cell. Engaging in important cellular processes such as DNA repair and cell death signaling, PARylation has gathered considerable interest as a target for genotoxic chemotherapy against cancer cells. To this end, various Poly(ADP-ribose) Polymerase (PARP) inhibitors have been developed to induce sensitivity to genotoxic stress in BRCA-mutated cancer cells, and Poly(ADP-ribose) Glycohydrolase (PARG) inhibition is investigated as an alternate pathway to PARP inhibition in genotoxic chemotherapy. However, little is known about the exact mode of interaction between PAR and different proteins mainly due to the fact that PARP produces polydisperse mixtures of PAR through a heterogeneous modification process. To tackle these problems, a controlled enzymatic synthesis pathway of PAR has been investigated through the use of masked β-NAD+ derivatives that can homogenously and monomerically modify PARP. In order to verify its ability to modify PARP, a sample of proparagyl-β-NAD+ derivative was used in an automodification assay with hTNKS-1. In addition, a PARG inhibitor prodrug in the form of an alanine-ester-masked ADP-HPM was developed as a cell-permeable PARG inhibitor to investigate its effect in a whole cell. In order to verify its activity, an in vitro experiment of the enzymatic cleavage of its masking group with HINT-1 was performed and the results were analyzed via LC/MS.","abstract_html":"Poly(ADP-ribosylation) (PARylation) is an important post-translational modification that maintains genomic stability in a cell. Engaging in important cellular processes such as DNA repair and cell death signaling, PARylation has gathered considerable interest as a target for genotoxic chemotherapy against cancer cells. To this end, various Poly(ADP-ribose) Polymerase (PARP) inhibitors have been developed to induce sensitivity to genotoxic stress in BRCA-mutated cancer cells, and Poly(ADP-ribose) Glycohydrolase (PARG) inhibition is investigated as an alternate pathway to PARP inhibition in genotoxic chemotherapy. However, little is known about the exact mode of interaction between PAR and different proteins mainly due to the fact that PARP produces polydisperse mixtures of PAR through a heterogeneous modification process. To tackle these problems, a controlled enzymatic synthesis pathway of PAR has been investigated through the use of masked β-NAD+ derivatives that can homogenously and monomerically modify PARP. In order to verify its ability to modify PARP, a sample of proparagyl-β-NAD+ derivative was used in an automodification assay with hTNKS-1. In addition, a PARG inhibitor prodrug in the form of an alanine-ester-masked ADP-HPM was developed as a cell-permeable PARG inhibitor to investigate its effect in a whole cell. In order to verify its activity, an in vitro experiment of the enzymatic cleavage of its masking group with HINT-1 was performed and the results were analyzed via LC/MS.","abstract_has_math":false,"creators":["Yang, Woojin"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"M.S.","degree_level":"Thesis","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Hergenrother, Paul J."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-07-07T19:58:21Z","date_published":"2016-07-07T19:58:21Z","updated_at":"2026-07-22T22:26:34Z","subjects":["PAR","Poly(ADP-ribose) Glycohydrolase (PARG)"],"languages":["en"],"rights":["Copyright 2016 Woojin Yang"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/90688","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Hergenrother, Paul J."]},{"key":"dc:creator","label":"Author","values":["Yang, Woojin"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2016-07-07T19:58:21Z","2016-04-28","2016-05"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M.S."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["PAR","Poly(ADP-ribose) Glycohydrolase (PARG)"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2016 Woojin Yang"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/90688"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Poly(ADP-ribosylation) (PARylation) is an important post-translational modification that maintains genomic stability in a cell. Engaging in important cellular processes such as DNA repair and cell death signaling, PARylation has gathered considerable interest as a target for genotoxic chemotherapy against cancer cells. To this end, various Poly(ADP-ribose) Polymerase (PARP) inhibitors have been developed to induce sensitivity to genotoxic stress in BRCA-mutated cancer cells, and Poly(ADP-ribose) Glycohydrolase (PARG) inhibition is investigated as an alternate pathway to PARP inhibition in genotoxic chemotherapy. However, little is known about the exact mode of interaction between PAR and different proteins mainly due to the fact that PARP produces polydisperse mixtures of PAR through a heterogeneous modification process. To tackle these problems, a controlled enzymatic synthesis pathway of PAR has been investigated through the use of masked β-NAD+ derivatives that can homogenously and monomerically modify PARP. In order to verify its ability to modify PARP, a sample of proparagyl-β-NAD+ derivative was used in an automodification assay with hTNKS-1. In addition, a PARG inhibitor prodrug in the form of an alanine-ester-masked ADP-HPM was developed as a cell-permeable PARG inhibitor to investigate its effect in a whole cell. In order to verify its activity, an in vitro experiment of the enzymatic cleavage of its masking group with HINT-1 was performed and the results were analyzed via LC/MS.","Submission original under an indefinite embargo labeled 'Open Access'. The submission was exported from vireo on 2016-07-07 without embargo terms","The student, Woojin Yang, accepted the attached license on 2016-04-28 at 09:55.","The student, Woojin Yang, submitted this Thesis for approval on 2016-04-28 at 10:06.","This Thesis was approved for publication on 2016-04-28 at 15:23.","DSpace SAF Submission Ingestion Package generated from Vireo submission #9568 on 2016-07-07 at 13:33:46","Made available in DSpace on 2016-07-07T19:58:21Z (GMT). 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Engaging in important cellular processes such as DNA repair and cell death signaling, PARylation has gathered considerable interest as a target for genotoxic chemotherapy against cancer cells. To this end, various Poly(ADP-ribose) Polymerase (PARP) inhibitors have been developed to induce sensitivity to genotoxic stress in BRCA-mutated cancer cells, and Poly(ADP-ribose) Glycohydrolase (PARG) inhibition is investigated as an alternate pathway to PARP inhibition in genotoxic chemotherapy. However, little is known about the exact mode of interaction between PAR and different proteins mainly due to the fact that PARP produces polydisperse mixtures of PAR through a heterogeneous modification process. To tackle these problems, a controlled enzymatic synthesis pathway of PAR has been investigated through the use of masked β-NAD+ derivatives that can homogenously and monomerically modify PARP. In order to verify its ability to modify PARP, a sample of proparagyl-β-NAD+ derivative was used in an automodification assay with hTNKS-1. In addition, a PARG inhibitor prodrug in the form of an alanine-ester-masked ADP-HPM was developed as a cell-permeable PARG inhibitor to investigate its effect in a whole cell. In order to verify its activity, an in vitro experiment of the enzymatic cleavage of its masking group with HINT-1 was performed and the results were analyzed via LC/MS.","Submission original under an indefinite embargo labeled 'Open Access'. The submission was exported from vireo on 2016-07-07 without embargo terms","The student, Woojin Yang, accepted the attached license on 2016-04-28 at 09:55.","The student, Woojin Yang, submitted this Thesis for approval on 2016-04-28 at 10:06.","This Thesis was approved for publication on 2016-04-28 at 15:23.","DSpace SAF Submission Ingestion Package generated from Vireo submission #9568 on 2016-07-07 at 13:33:46","Made available in DSpace on 2016-07-07T19:58:21Z (GMT). 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