R-Loop Formation in Meiosis: Roles in Meiotic Transcription-Associated DNA Damage

Fujiwara, Yasuhiro; Handel, Mary Ann; Okada, Yuki

doi:10.3390/epigenomes6030026

Cited by 4 publications

References 118 publications

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DNA cytosine methyltransferases differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei meiosis

Jovanska,

Lin,

Yao

et al. 2024

Nucleic Acids Research

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Trichoderma reesei is an economically important enzyme producer with several unique meiotic features. spo11, the initiator of meiotic double-strand breaks (DSBs) in most sexual eukaryotes, is dispensable for T. reesei meiosis. T. reesei lacks the meiosis-specific recombinase Dmc1. Rad51 and Sae2, the activator of the Mre11 endonuclease complex, promote DSB repair and chromosome synapsis in wild-type and spo11Δ meiosis. DNA methyltransferases (DNMTs) perform multiple tasks in meiosis. Three DNMT genes (rid1, dim2 and dimX) differentially regulate genome-wide cytosine methylation and C:G-to-T:A hypermutations in different chromosomal regions. We have identified two types of DSBs: type I DSBs require spo11 or rid1 for initiation, whereas type II DSBs do not rely on spo11 and rid1 for initiation. rid1 (but not dim2) is essential for Rad51-mediated DSB repair and normal meiosis. rid1 and rad51 exhibit a locus heterogeneity (LH) relationship, in which LH-associated proteins often regulate interconnectivity in protein interaction networks. This LH relationship can be suppressed by deleting dim2 in a haploid rid1Δ (but not rad51Δ) parental strain, indicating that dim2 and rid1 share a redundant function that acts earlier than rad51 during early meiosis. In conclusion, our studies provide the first evidence of the involvement of DNMTs during meiotic initiation and recombination.

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DNA cytosine methyltransferases differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei meiosis

Jovanska,

Lin,

Yao

et al. 2024

Nucleic Acids Research

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Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis

Miao

Guo

Williams

et al. 2023

Preprint

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Persistence of unrepaired DNA damage in oocytes is detrimental and may cause genetic aberrations, miscarriage, and infertility. RPA, an ssDNA-binding complex, is essential for various DNA-related processes. Here we report that RPA plays a novel role in DNA damage repair during postnatal oocyte development after meiotic recombination. To investigate the role of RPA during oogenesis, we inactivated RPA1 (replication protein A1), the largest subunit of the heterotrimeric RPA complex, specifically in oocytes using two germline-specific Cre drivers (Ddx4-Cre and Zp3-Cre). We find that depletion of RPA1 leads to the disassembly of the RPA complex, as evidenced by the absence of RPA2 and RPA3 in RPA1-deficient oocytes. Strikingly, severe DNA damage occurs in RPA1-deficient GV-stage oocytes. Loss of RPA in oocytes triggered the canonical DNA damage response mechanisms and pathways, such as activation of ATM, ATR, DNA-PK, and p53. In addition, the RPA deficiency causes chromosome misalignment at metaphase I and metaphase II stages of oocytes, which is consistent with altered transcript levels of genes involved in cytoskeleton organization in RPA1-deficient oocytes. Absence of the RPA complex in oocytes severely impairs folliculogenesis and leads to a significant reduction in oocyte number and female infertility. Our results demonstrate that RPA plays an unexpected role in DNA damage repair during mammalian folliculogenesis.

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The role of p53 in male infertility

Li,

Huang,

Luo

et al. 2024

Front. Endocrinol.

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The tumor suppressor p53 is a transcription factor involved in a variety of crucial cellular functions, including cell cycle arrest, DNA repair and apoptosis. Still, a growing number of studies indicate that p53 plays multiple roles in spermatogenesis, as well as in the occurrence and development of male infertility. The representative functions of p53 in spermatogenesis include the proliferation of spermatogonial stem cells (SSCs), spermatogonial differentiation, spontaneous apoptosis, and DNA damage repair. p53 is involved in various male infertility-related diseases. Innovative therapeutic strategies targeting p53 have emerged in recent years. This review focuses on the role of p53 in spermatogenesis and male infertility and analyses the possible underlying mechanism involved. All these conclusions may provide a new perspective on drug intervention targeting p53 for male infertility treatment.

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R-Loop Formation in Meiosis: Roles in Meiotic Transcription-Associated DNA Damage

Cited by 4 publications

References 118 publications

DNA cytosine methyltransferases differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei meiosis

DNA cytosine methyltransferases differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei meiosis

Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis

The role of p53 in male infertility

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