Novel BRCA1–PLK1–CIP2A axis orchestrates homologous recombination-mediated DNA repair to maintain chromosome integrity during oocyte meiosis DOI Creative Commons
Crystal Lee, Jeong Su Oh

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Double-strand breaks (DSBs) are a formidable threat to genome integrity, potentially leading cancer and various genetic diseases. The prolonged lifespan of mammalian oocytes increases their susceptibility DNA damage over time. While somatic cells suppress DSB repair during mitosis, exhibit remarkable capacity DSBs meiotic maturation. However, the precise mechanisms underlying in remain poorly understood. Here, we describe pivotal role BRCA1-PLK1-CIP2A axis safeguarding genomic integrity maturation oocytes. We found that inhibition homologous recombination (HR) severely impaired chromosome by generating fragments Notably, HR recruitment CIP2A damaged chromosomes, depletion led fragmentation following induction. Moreover, BRCA1 chromosomal CIP2A, but not vice versa. Importantly, could be rescued PLK1 inhibition. Consequently, our findings only underscore importance preventing fragmentation, also demonstrate regulatory this process oocyte

Language: Английский

Does gonadotoxic chemotherapy deplete the ovarian reserve through activation of primordial follicles? DOI
Murat Erden,

Kutluk Oktay

Human Reproduction, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Abstract Despite significant advances in fertility preservation, no proven pharmacological options exist to protect ovarian primordial follicle reserve from chemotherapy-induced damage. Developing targeted gonadoprotective treatments will require an improved understanding of the molecular mechanisms underlying depletion. While there is robust evidence that gonadotoxic chemotherapy induces death by causing DNA double-strand breaks which trigger apoptotic death, activation leading ‘burn-out’ has been suggested as alternative mechanism. Here, we critically evaluated whether a mechanism depletion humans. We assessed causal relationship between exposure and applying Bradford Hill criteria.

Language: Английский

Citations

1
COX15 deficiency causes oocyte ferroptosis DOI Creative Commons
Zhihua Zhang, Ran Yu,

Qiuwen Shi

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(45)

Published: Oct. 29, 2024

Mitochondria play diverse roles in mammalian physiology. The architecture, activity, and physiological functions of mitochondria oocytes are largely different from those somatic cells, but the mitochondrial proteins related to oocyte quality reproductive longevity remain unknown. Here, using whole-exome sequencing data 1,024 women (characterized by maturation arrest degenerated or morphologically abnormal oocytes) 2,868 healthy controls, we performed a population gene-based burden test for genes identified candidate gene, cytochrome c oxidase assembly protein 15 (

Language: Английский

Citations

3
Oocyte‐specific deletion of eukaryotic translation initiation factor 5 causes apoptosis of mouse oocytes within the early‐growing follicles by mitochondrial fission defect‐reactive oxygen species‐DNA damage DOI Creative Commons
Weiyong Wang, Huiyu Liu, Shuang Liu

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(8)

Published: Aug. 1, 2024

Abstract Background Mutations in several translation initiation factors are closely associated with premature ovarian insufficiency (POI), but the underlying pathogenesis remains largely unknown. Methods and results We generated eukaryotic factor 5 ( Eif5 ) conditional knockout mice aiming to investigate function of eIF5 during oocyte growth follicle development. Here, we demonstrated that deletion mouse primordial growing oocytes both resulted apoptosis within early‐growing follicles. Further studies revealed downregulated levels mitochondrial fission‐related proteins (p‐DRP1, FIS1, MFF MTFR) upregulated integrated stress response‐related (AARS1, SHMT2 SLC7A1) genes Atf4 , Ddit3 Fgf21 ). Consistent this, dysfunction characterized by elongated form, aggregated distribution beneath membrane, decreased adenosine triphosphate content mtDNA copy numbers, excessive accumulation reactive oxygen species (ROS) superoxide. Meanwhile, led a significant increase DNA damage response (γH2AX, p‐CHK2 p‐p53) proapoptotic (PUMA BAX), as well decrease anti‐apoptotic protein BCL‐xL. Conclusion These findings indicate follicles via fission defects, ROS damage. This study provides new insights into pathogenesis, genetic diagnosis potential therapeutic targets for POI. Key points leads arrest impairs proteins, followed dysfunction. Depletion causes pathway.

Language: Английский

Citations

2
Equol promotes the in vitro maturation of porcine oocytes by activating the NRF2/KEAP1 signaling pathway DOI

Sai Jin Xiao,

Ke Peng, Rui Chen

et al.

Theriogenology, Journal Year: 2024, Volume and Issue: 233, P. 70 - 79

Published: Nov. 22, 2024

Language: Английский

Citations

2
CELL CYCLE DYSREGULATION IN CANCER DOI
Antonino Glaviano, Samarendra Kumar Singh, E. Hui Clarissa Lee

et al.

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 77(2), P. 100030 - 100030

Published: Dec. 24, 2024

Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated growth. Genetic mutations can determine tumor onset by either augmenting division rates or restraining normal controls such as arrest apoptosis. As result, cells not only undergo uncontrolled but also become compromised in their ability to exit the accurately. Regulation progression enabled specific surveillance mechanisms known checkpoints, aberrations these signaling pathways often culminate cancer. For instance, DNA damage which preclude generation augmentation G1, S, G2 phases, are defective cancer cells, allowing spite accumulation genetic errors. Notably, tumors have evolved dependent on checkpoints for survival. example, checkpoint replication stress mitotic rarely remain intact because any could result irreparable catastrophic chromosomal missegregation leading death. In this review, we initially focus control functions involved then proceed examine how provide new therapeutic windows that be exploited therapy. SIGNIFICANCE STATEMENT: Conversely, missegregation, This review focuses an emerging understanding opportunities

Language: Английский

Citations

2
The DNA double-strand break repair proteins γH2AX, RAD51, BRCA1, RPA70, KU80, and XRCC4 exhibit follicle-specific expression differences in the postnatal mouse ovaries from early to older ages DOI Creative Commons
Günel Talibova,

Yesim Bilmez,

Betul Tire

et al.

Journal of Assisted Reproduction and Genetics, Journal Year: 2024, Volume and Issue: 41(9), P. 2419 - 2439

Published: July 18, 2024

Ovarian aging is closely related to a decrease in follicular reserve and oocyte quality. The precise molecular mechanisms underlying these reductions have yet be fully elucidated. Herein, we examine spatiotemporal distribution of key proteins responsible for DNA double-strand break (DSB) repair ovaries from early older ages. Functional studies shown that the γH2AX, RAD51, BRCA1, RPA70 play indispensable roles HR-based pathway, while KU80 XRCC4 are essential successfully operating cNHEJ pathway.

Language: Английский

Citations

0
Novel BRCA1–PLK1–CIP2A axis orchestrates homologous recombination-mediated DNA repair to maintain chromosome integrity during oocyte meiosis DOI Creative Commons
Crystal Lee, Jeong Su Oh

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Double-strand breaks (DSBs) are a formidable threat to genome integrity, potentially leading cancer and various genetic diseases. The prolonged lifespan of mammalian oocytes increases their susceptibility DNA damage over time. While somatic cells suppress DSB repair during mitosis, exhibit remarkable capacity DSBs meiotic maturation. However, the precise mechanisms underlying in remain poorly understood. Here, we describe pivotal role BRCA1-PLK1-CIP2A axis safeguarding genomic integrity maturation oocytes. We found that inhibition homologous recombination (HR) severely impaired chromosome by generating fragments Notably, HR recruitment CIP2A damaged chromosomes, depletion led fragmentation following induction. Moreover, BRCA1 chromosomal CIP2A, but not vice versa. Importantly, could be rescued PLK1 inhibition. Consequently, our findings only underscore importance preventing fragmentation, also demonstrate regulatory this process oocyte

Language: Английский

Citations

0