Biology subjects

Ojarikre, O.

Publications and source records attributed to Ojarikre, O..

3 recordsLinked to original sources

bioRxiv2026

Stage-specific checkpoint signalling by ATM, ATR and DNA-PK safeguards oocyte genome integrity

In somatic cells, DNA double-strand breaks (DSBs) are potentially catastrophic lesions that activate phosphatidylinositol 3-kinase-related kinase (PIKK) signalling to promote DNA repair or eliminate damaged cells. During meiosis, however, DSBs are deliberately generated as essential intermediates in homologous recombination, raising the question of how DNA damage signalling distinguishes programmed recombination from genome instability. To define how PIKK signalling is adapted to these distinct contexts, we resolved the function of the three PIKKs ATM, ATR and DNA-PK in physiological meiotic recombination and the response to postnatal DNA damage in mouse oocytes. Following postnatal irradiation, ATM functions as the dominant response kinase, with ATR and DNA-PK acting redundantly to eliminate damaged oocytes. In contrast, meiotic surveillance is mediated by ATR, with ATR removal rescuing oocyte loss in response to asynapsis and, independently, to persistent meiotic DSBs. Our findings demonstrate that DNA damage signalling is developmentally reconfigured during oogenesis and highlight distinct pathways of oocyte elimination that may ultimately inform strategies to maintain the ovarian reserve in mammals.

molecular biology↗

bioRxiv2024

Systematic identification of Y-chromosome gene functions in mouse spermatogenesis

The mammalian Y chromosome is essential for male fertility, but how individual Y genes regulate spermatogenesis is poorly understood. To resolve this question, we generate a deletion series of the mouse Y chromosome, creating thirteen Y-deletant mouse models and conducting exhaustive reproductive phenotyping. Eight Y genes, including several that are deeply conserved and exhibit testis-specific expression, are dispensable for spermatogenesis. For others, we uncover novel functions, including a role for Uty in establishment and differentiation of spermatogonia, and for Zfy2 in ensuring meiotic pairing and reciprocal recombination between the sex chromosomes. We also generate the first mouse equivalent of the human infertility AZFa deletion, revealing cumulative detrimental effects of Y-gene loss on spermatogenesis. We use single nuclei RNAseq to identify candidate mechanisms by which Y genes regulate the germ cell transcriptome and reveal an unexpected impact of Y genes on testis supporting cells. Our study represents a paradigm for the complete functional dissection of a mammalian Y chromosome and advances our knowledge of human infertility and Y-chromosome evolution.

genetics↗

bioRxiv2017

ATR is a multifunctional regulator of male mouse meiosis

Meiotic cells undergo genetic exchange between homologous chromosomes through programmed DNA double-strand break (DSB) formation, recombination and synapsis1, 2. In mice, the DNA damage-regulated phosphatidylinositol-3-kinase-like kinase (PIKK) ATM regulates all of these processes3-6. However, the meiotic functions of another major PIKK, ATR, have remained elusive, because germ line-specific depletion of this kinase is challenging. Using an efficient conditional strategy, we uncover roles for ATR in male mouse prophase I progression. Deletion of ATR causes chromosome axis fragmentation and germ cell elimination at mid pachynema. ATR is required for homologous synapsis, in a manner genetically dissociable from DSB formation. In addition, ATR regulates loading of recombinases RAD51 and DMC1 to DSBs and maintenance of recombination foci on synapsed and asynapsed chromosomes. Mid pachytene spermatocyte elimination in ATR deficient mice cannot be rescued by deletion of ATM and the third DNA damage-regulated PIKK, PRKDC, consistent with the existence of a PIKK-independent surveillance mechanism in the mammalian germ line. Our studies identify ATR as a multifunctional regulator of mouse meiosis.

cell biology↗