Browsing by keyword "recombination"
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Signaling to TRP53 and TAp63 from CHK1/CHK2 is responsible for elimination of most oocytes defective for either chromosome synapsis or recombination [preprint]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.
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Structure of germline immunoglobulin heavy-chain gamma 1 transcripts in interleukin 4 treated mouse spleen cellsAntibody class switching is mediated by a DNA recombination event that replaces the C mu gene with one of the other heavy (H) chain constant region (CH) genes located 3' to the C mu gene. The regulation of this process is essential to the immune response because different CH regions provide different biological functions. Correlative evidence indicates that the isotype (class) specificity of the switch is determined by the accessibility of specific CH genes as indicated by hypomethylation and transcriptional activity. For example, RNAs transcribed from specific unrearranged CH genes are induced prior to switching under conditions that promote subsequent switching to these same CH genes. The function of transcription of these germline CH genes is unknown. In this report, we describe the structure of RNA transcribed from unrearranged gamma 1 genes in mouse spleen cells treated with LPS plus a HeLa cell supernatant containing recombinant interleukin 4. The germline gamma 1 RNA is initiated at multiple start sites 5' to the tandem repeats of the gamma 1 switch (S gamma 1) region. As is true for analogous RNAs transcribed from unrearranged gamma 2b and alpha genes, the germline gamma 1 RNA has an I exon transcribed from the region 5' to S gamma 1 sequences, which is spliced at a unique site to the C gamma gene. The germline gamma 1 RNA has an open-reading frame (ORF) that potentially encodes a small protein 48 amino acid in length.
