University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2019-09-12
Document Type
Article Preprint
Disciplines
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Enzymes and Coenzymes | Genetic Phenomena | Genetics
Abstract
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. 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.
Keywords
Genetics, oocytes, chromosome synapsis, recombination, mutation
Rights and Permissions
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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.
DOI of Published Version
10.1101/768150
Source
bioRxiv 768150; doi: https://doi.org/10.1101/768150. Link to preprint on bioRxiv service.
Journal/Book/Conference Title
bioRxiv
Repository Citation
Rinaldi VD, Bloom JC, Schimenti JC. (2019). Signaling to TRP53 and TAp63 from CHK1/CHK2 is responsible for elimination of most oocytes defective for either chromosome synapsis or recombination. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/768150. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1631
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemistry, Biophysics, and Structural Biology Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Genetics Commons