Lack of Rev7 function results in development of tubulostromal adenomas in mouse ovary

Abbasi, Abdolrahim; Khalaj, Maryam; Akiyama, Kouyou; Mukai, Yoshiyuki; Matsumoto, Hirokazu; Acosta, Tomás J.; Said, Neveen; Yoshida, Midori; Kunieda, Tetsuo

doi:10.1016/j.mce.2015.05.022

Cited by 9 publications

(6 citation statements)

References 28 publications

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“…The Rev7 mutant induces Mad2 deficiency, mediates mitotic arrest and accumulates DNA damage, which increases the frequency of spindle aberrations and chromosome lags. 25 In our study, Nsun5 knockout increased the rate of spindle/chromosome defects (Figure 2 ). Our results suggested a regulatory mechanism by which m 5 C modification deletion decreased the protein level of MAD2L2 and accelerated the loss of MAD2L2 mRNA stability, which caused a deficiency in ovarian function (Figure 5 ).…”

Section: Discussionsupporting

confidence: 57%

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RNA‐methyltransferase Nsun5 controls the maternal‐to‐zygotic transition by regulating maternal mRNA stability

Ding

et al. 2022

Clinical & Translational Med

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Background RNA modification‐induced ovarian dysgenesis appears to be necessary for ovary development. However, how m 5 C (5‐methylcytosine)‐coordinating modificatory transcripts are dynamically regulated during oogenesis, and ovarian development is unknown. The purpose of this study was to determine whether NOP2/Sun RNA methyltransferase 5 (Nsun5) deletion leads to suppression of ovarian function and arrest of embryonic development. The regulation of mRNA decay and stability by m 5 C modification is essential at multiple stages during the maternal‐to‐zygotic (MZT) transition. Methods Mouse ovaries and oocytes with Nsun5 KO and the KGN cell line were subjected to m 5 C identification, alternative splicing analysis and protein expression. BS‐m 5 C‐seq, real‐time polymerase chain reaction, Western blot, immunofluorescence and actinomycin D treatment assays were used. In particular, BS‐m 5 C‐seq revealed a dynamic pattern of m 5 C sites and genes in the ovaries between Nsun5 KO and WT mice at the 2‐month and 6‐month stages. Diverse bioinformatic tools were employed to identify target genes for Nsun5. Results Here, a maternal mRNA stability study showed that deletion of the m 5 C methyltransferase Nsun5 obstructs follicular development and ovarian function, which leads directly to inhibition of embryogenesis and embryo development. Dynamic analysis of m 5 C revealed that the level of m 5 C decreased in a time‐dependent manner after Nsun5 knockout. Regarding the molecular mechanism, we found that Nsun5 deficiency caused a m 5 C decline in the exon and 3′UTR regions that influenced the translation efficiency of Mitotic arrest deficient 2 like 2 (MAD2L2) and Growth differentiation factor 9 (GDF9) in the ovary. Mechanistic investigation of alternative splicing indicated that Nsun5 KO triggers aberrant events in the exon region of Brd8 . Conclusions Nsun5 loss arrests follicular genesis and development in ovarian aging, indicating that Nsun5/m 5 C‐regulated maternal mRNA stabilization is essential for MZT transition.

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Section: Discussionsupporting

confidence: 57%

“…The Rev7 mutant induces Mad2 deficiency, mediates mitotic arrest and accumulates DNA damage, which increases the frequency of spindle aberrations and chromosome lags 25 . In our study, Nsun5 knockout increased the rate of spindle/chromosome defects (Figure 2).…”

Section: Discussionsupporting

confidence: 55%

RNA‐methyltransferase Nsun5 controls the maternal‐to‐zygotic transition by regulating maternal mRNA stability

Ding

et al. 2022

Clinical & Translational Med

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“…Additionally, Sergey Karakashev et al discovered that inhibition of EZH2 upregulates MAD2L2, potentially enhancing the efficacy of PARP inhibitors in CARM1-dependent OVCA 18 . Furthermore, Abdolrahim Abbasi et al proposed that mutations in MAD2L2 might contribute to developing OVCA in a mouse model 19 .…”

Section: Discussionmentioning

confidence: 99%

MAD2L2, a key regulator in ovarian cancer and promoting tumor progression

Xu,

Zheng,

Shi

et al. 2024

Sci Rep

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Ovarian cancer (OVCA), a prevalent gynecological malignancy, ranks as the fourth most common cancer among women. Mitotic Arrest Deficient 2 Like 2 (MAD2L2), a chromatin-binding protein and a component of DNA polymerase ζ, has been previously identified as an inhibitor of tumor growth in colorectal cancer. However, the roles of MAD2L2 in OVCA, including its expression, impact, and prognostic significance, remain unclear. We employed bioinformatics tools, Cox Regression analysis, and in vitro cell experiments to investigate its biological functions. Our findings reveal that MAD2L2 typically undergoes genomic alterations, such as amplifications and deep deletions. Moreover, we observed an overexpression of MAD2L2 mRNA in OVCA patients, correlating with reduced survival rates, particularly in those with Grade IV tumors. Furthermore, analysis of mRNA biofunctions indicated that MAD2L2 is predominantly localized in the organellar ribosome, engaging mainly in NADH dehydrogenase activity. This was deduced from the results of gene ontology enrichment analysis, which also identified its role as a structural constituent in mitochondrial translation elongation. These findings were corroborated by KEGG pathway analysis, further revealing MAD2L2’s involvement in tumor metabolism and the cell death process. Notably, MAD2L2 protein expression showed significant associations with various immune cells, including CD4+T cells, CD8+T cells, B cells, natural killer cells, and Myeloid dendritic cells. Additionally, elevated levels of MAD2L2 were found to enhance cell proliferation and migration in OVCA cells. The upregulation of MAD2L2 also appears to inhibit the ferroptosis process, coinciding with increased mTOR signaling activity in these cells. Our study identifies MAD2L2 as a novel regulator in ovarian tumor progression and offers new insights for treating OVCA.

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“…Considering the biological role of REV7 in DNA damage-induced mutagenesis, dysregulated REV7 expression is supposed to promote cancer development via the introduction of mutations in cancer-related genes or in regions of epigenetic regulation, although there is no direct evidence showing the relationship between REV7 expression and cancer development thus far. Conversely, Rev7 C70R/C70R mutant mice, in which mutant REV7 is unable to interact with REV3, causing germ cell aplasia after birth in both males and females, develop tubulostromal adenomas in the ovary, in which an increase in gonadotropin levels and accumulation of DNA damage may contribute to tumor development [ 83 , 84 ]. Notably, REV7 is a causative gene of FA, which shows a predisposition for the development of hematological malignancy [ 74 ].…”

Section: Rev7 In Cancermentioning

confidence: 99%

REV7 in Cancer Biology and Management

Murakumo

Sakurai

Kato

et al. 2023

Cancers

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DNA repair and cell cycle regulation are potential biological fields to develop molecular targeting therapies for cancer. Human REV7 was originally discovered as a homologous molecule to yeast Rev7, which is involved in DNA damage response and mutagenesis, and as the second homolog of yeast Mad2, involved in the spindle assembly checkpoint. Although REV7 principally functions in the fields of DNA repair and cell cycle regulation, many binding partners of REV7 have been identified using comprehensive analyses in the past decade, and the significance of REV7 is expanding in various other biological fields, such as gene transcription, epigenetics, primordial germ cell survival, neurogenesis, intracellular signaling, and microbial infection. In addition, the clinical significance of REV7 has been demonstrated in studies using human cancer tissues, and investigations in cancer cell lines and animal models have revealed the greater impacts of REV7 in cancer biology, which makes it an attractive target molecule for cancer management. This review focuses on the functions of REV7 in human cancer and discusses the utility of REV7 for cancer management with a summary of the recent development of inhibitors targeting REV7.

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Lack of Rev7 function results in development of tubulostromal adenomas in mouse ovary

Cited by 9 publications

References 28 publications

RNA‐methyltransferase Nsun5 controls the maternal‐to‐zygotic transition by regulating maternal mRNA stability

RNA‐methyltransferase Nsun5 controls the maternal‐to‐zygotic transition by regulating maternal mRNA stability

MAD2L2, a key regulator in ovarian cancer and promoting tumor progression

REV7 in Cancer Biology and Management

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