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dc.contributor.authorRinaldi, Vera D.
dc.contributor.authorBloom, Jordana C.
dc.contributor.authorSchimenti, John C.
dc.date2022-08-11T08:08:24.000
dc.date.accessioned2022-08-23T15:53:41Z
dc.date.available2022-08-23T15:53:41Z
dc.date.issued2019-09-12
dc.date.submitted2019-09-23
dc.identifier.citation<p>bioRxiv 768150; doi: https://doi.org/10.1101/768150. <a href="https://doi.org/10.1101/768150" target="_blank">Link to preprint on bioRxiv service.</a></p>
dc.identifier.doi10.1101/768150
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29402
dc.description.abstractEukaryotic organisms have evolved mechanisms to prevent the accumulation of cells bearing genetic aberrations. This is especially crucial for the germline, because fecundity, and fitness of progeny would be adversely affected by an excessively high mutational incidence. The process of meiosis poses unique problems for mutation avoidance, due to the requirement for SPO11-induced programmed double strand breaks (DSBs) in recombination-driven pairing and segregation of homologous chromosomes. Mouse meiocytes bearing unrepaired meiotic DSBs or unsynapsed chromosomes are eliminated before completing meiotic prophase I. In previous work, we showed that checkpoint kinase 2 (CHK2; CHEK2), a canonical DNA damage response protein, is crucial for eliminating not only oocytes defective in meiotic DSB repair (e.g. Trip13Gt mutants), but also asynaptic Spo11−/− oocytes that accumulate a threshold level of spontaneous DSBs. However, rescue of such oocytes by Chk2 deficiency was incomplete, raising the possibility that a parallel checkpoint pathway(s) exists. Here, we show that mouse oocytes lacking both TAp63 and TRP53 protects nearly all Spo11−/− and Trip13Gt/Gt oocytes from elimination. We present evidence that checkpoint kinase I (CHK1; CHEK1), which is known to signal to TRP53, also becomes activated by persistent DSBs in oocytes, and to an increased degree when CHK2 is absent. The combined data indicate that nearly all oocytes reaching a threshold level of unrepaired DSBs are eliminated by a semi-redundant pathway of CHK1/CHK2 signaling to TRP53/TAp63.
dc.language.isoen_US
dc.rightsThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectGenetics
dc.subjectoocytes
dc.subjectchromosome synapsis
dc.subjectrecombination
dc.subjectmutation
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectEnzymes and Coenzymes
dc.subjectGenetic Phenomena
dc.subjectGenetics
dc.titleSignaling to TRP53 and TAp63 from CHK1/CHK2 is responsible for elimination of most oocytes defective for either chromosome synapsis or recombination [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2640&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1631
dc.identifier.contextkey15400195
refterms.dateFOA2022-08-23T15:53:41Z
html.description.abstract<p>Eukaryotic organisms have evolved mechanisms to prevent the accumulation of cells bearing genetic aberrations. This is especially crucial for the germline, because fecundity, and fitness of progeny would be adversely affected by an excessively high mutational incidence. The process of meiosis poses unique problems for mutation avoidance, due to the requirement for SPO11-induced programmed double strand breaks (DSBs) in recombination-driven pairing and segregation of homologous chromosomes. Mouse meiocytes bearing unrepaired meiotic DSBs or unsynapsed chromosomes are eliminated before completing meiotic prophase I. In previous work, we showed that checkpoint kinase 2 (CHK2; CHEK2), a canonical DNA damage response protein, is crucial for eliminating not only oocytes defective in meiotic DSB repair (e.g. <em>Trip13</em><sup><em>Gt</em></sup> mutants), but also asynaptic <em>Spo11</em><sup>−/−</sup> oocytes that accumulate a threshold level of spontaneous DSBs. However, rescue of such oocytes by <em>Chk2</em> deficiency was incomplete, raising the possibility that a parallel checkpoint pathway(s) exists. Here, we show that mouse oocytes lacking both TAp63 and TRP53 protects nearly all <em>Spo11</em><sup>−/−</sup> and <em>Trip13</em><sup><em>Gt/Gt</em></sup> oocytes from elimination. We present evidence that checkpoint kinase I (CHK1; CHEK1), which is known to signal to TRP53, also becomes activated by persistent DSBs in oocytes, and to an increased degree when CHK2 is absent. The combined data indicate that nearly all oocytes reaching a threshold level of unrepaired DSBs are eliminated by a semi-redundant pathway of CHK1/CHK2 signaling to TRP53/TAp63.</p>
dc.identifier.submissionpathfaculty_pubs/1631
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology


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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.