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dc.contributor.advisorSharon Cantor
dc.contributor.authorPanzarino, Nicholas J.
dc.date2022-08-11T08:08:39.000
dc.date.accessioned2022-08-23T16:02:48Z
dc.date.available2022-08-23T16:02:48Z
dc.date.issued2021-04-02
dc.date.submitted2021-04-29
dc.identifier.doi10.13028/02f0-tw38
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31361
dc.description.abstractCancers that are deficient in BRCA1 or BRCA2 are thought to be hypersensitive to genotoxic agents because they cannot prevent or repair DNA double strand breaks, but observations in patients suggest this dogma may no longer agree with experiment. Here, we propose that single stranded DNA underlies the hypersensitivity of BRCA deficient cancers, and that defects in double strand break repair and prevention do not. Specifically, in BRCA deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. In addition, we observed gaps could be suppressed by either restored fork restraint or by gap filling, both of which conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored double strand break repair and prevention did not confer therapy resistance when gaps were present. Critically, double strand breaks were not detected after therapy when apoptosis was inhibited, supporting a framework in which double strand breaks are not directly induced by genotoxic agents, but instead are created by cell death nucleases and are not fundamental to genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, "BRCAness," and we propose are fundamental to the mechanism-of-action of genotoxic chemotherapy.
dc.language.isoen_US
dc.rightsLicensed under a Creative Commons license
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCancer
dc.subjectBRCAness
dc.subjectssDNA
dc.subjectGenotoxin
dc.subjectPARPi
dc.subjectAcquired Resistance
dc.subjectCancer Biology
dc.subjectCell Biology
dc.titleThe ssDNA Theory of BRCAness and Genotoxic Agents
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2140&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/1131
dc.legacy.embargo2021-04-29T00:00:00-07:00
dc.identifier.contextkey22714195
refterms.dateFOA2022-08-30T15:30:33Z
html.description.abstract<p>Cancers that are deficient in BRCA1 or BRCA2 are thought to be hypersensitive to genotoxic agents because they cannot prevent or repair DNA double strand breaks, but observations in patients suggest this dogma may no longer agree with experiment. Here, we propose that single stranded DNA underlies the hypersensitivity of BRCA deficient cancers, and that defects in double strand break repair and prevention do not. Specifically, in BRCA deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. In addition, we observed gaps could be suppressed by either restored fork restraint or by gap filling, both of which conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored double strand break repair and prevention did not confer therapy resistance when gaps were present. Critically, double strand breaks were not detected after therapy when apoptosis was inhibited, supporting a framework in which double strand breaks are not directly induced by genotoxic agents, but instead are created by cell death nucleases and are not fundamental to genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, "<em>BRCAness</em>," and we propose are fundamental to the mechanism-of-action of genotoxic chemotherapy.</p>
dc.identifier.submissionpathgsbs_diss/1131
dc.contributor.departmentMolecular, Cell and Cancer Biology
dc.description.thesisprogramCancer Biology
dc.identifier.orcid0000-0002-5274-3901


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