DNA repair protein FANCD2 has both ubiquitination-dependent and ubiquitination-independent functions during germ cell development

Zhao, Simin; Huang, Chengzi; Yang, Yajuan; Xu, Weiwei; Yu, Yongze; Wen, Canxin; Cao, Lili; Gao, Fei; Qin, Yingying; Chen, Zi‐Jiang; Guo, Ting; Zhao, Shidou

doi:10.1016/j.jbc.2023.102905

“…This independent function of FANCD2/FANCI is a crucial checkpoint for tumor cells as they disproportionately depend on the G2/M checkpoint to avoid mitotic disasters [ 48 , 49 ]. These groundbreaking discoveries align with previous research on post-translational modifications of FANCD2, such as phosphorylation and ubiquitination, which also participate intricately in DNA damage repair [ 50 ], regulation of the cell cycle [ 51 ], apoptosis [ 52 ], and chromatin remodeling [ 53 ]. Moreover, these modifications are closely associated with cellular growth, differentiation, and the maintenance of normal physiological functions within an organism.…”

Section: Discussionsupporting

confidence: 69%

Pancancer analysis of the prognostic and immunological role of FANCD2: a potential target for carcinogenesis and survival

Zhao,

Wang,

Wang

et al. 2024

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Recent evidence has shed light on the significant role of FANCD2 in cancer initiation, development, and progression. However, a comprehensive pan-cancer analysis of FANCD2 has been lacking. In this study, we have conducted a thorough investigation into the expression profiles and prognostic significance of FANCD2, as well as its correlation with clinicopathological parameters and immune cell infiltration, using advanced bioinformatic techniques. The results demonstrate that FANCD2 is significantly upregulated in various common cancers and is associated with prognosis. Notably, higher expression levels of FANCD2 are linked to poor overall survival, as indicated by Cox regression and Kaplan-Meier analyses. Additionally, we have observed a decrease in the methylation of FANCD2 DNA in some cancers, and this decrease is inversely correlated with FANCD2 expression. Genetic alterations in FANCD2 predominantly manifest as mutations, which are associated with overall survival, disease-specific survival, disease-free survival, and progression-free survival in certain tumor types. Moreover, FANCD2 exhibits a strong correlation with infiltrating cell levels, immune checkpoint genes, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analysis further highlights the potential impact of FANCD2 on Fanconi anemia (FA) pathway and cell cycle regulation. Through this comprehensive pan-cancer analysis, we have gained a deeper understanding of the functions of FANCD2 in oncogenesis and metastasis across different types of cancer.

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“…This independent function of FANCD2/FANCI is a crucial checkpoint for tumor cells as they disproportionately depend on the G2/M checkpoint to avoid mitotic disasters [48,49] . These groundbreaking discoveries align with previous research on posttranslational modi cations of FANCD2, such as phosphorylation and ubiquitination, which also participate intricately in DNA damage repair [50] , regulation of the cell cycle [51] ,apoptosis [52] , and chromatin remodeling [53] . Moreover, these modi cations are closely associated with cellular growth, differentiation, and the maintenance of normal physiological functions within an organism.…”

Section: Discussionsupporting

confidence: 74%

Pancancer Analysis of the Prognostic and immunological Role of FANCD2: A Potential Target for Carcinogenesis and Survival

zhao,

Wang,

Wang

et al. 2023

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0

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Recent evidence has shed light on the significant role of FANCD2 in cancer initiation, development, and progression. However, a comprehensive pan-cancer analysis of FANCD2 has been lacking. In this study, we have conducted a thorough investigation into the expression profiles and prognostic significance of FANCD2, as well as its correlation with clinicopathological parameters and immune cell infiltration, using advanced bioinformatic techniques. The results demonstrate that FANCD2 is significantly upregulated in various common cancers and is associated with prognosis. Notably, higher expression levels of FANCD2 are linked to poor overall survival, as indicated by Cox regression and Kaplan-Meier analyses. Additionally, we have observed a decrease in the methylation of FANCD2 DNA in some cancers, and this decrease is inversely correlated with FANCD2 expression. Genetic alterations in FANCD2 predominantly manifest as mutations, which are associated with overall survival, disease-specific survival, disease-free survival, and progression-free survival in certain tumor types. Moreover, FANCD2 exhibits a strong correlation with infiltrating cell levels, immune checkpoint genes, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analysis further highlights the potential impact of FANCD2 on Fanconi anemia (FA) pathway and cell cycle regulation. Through this comprehensive pan-cancer analysis, we have gained a deeper understanding of the functions of FANCD2 in oncogenesis and metastasis across different types of cancer.

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“…In this study, we first constructed Faap100 knockout mouse model and found Faap100 −/− mice had hypogonadism with a dramatic reduction of PGCs from E9.5, a time before entering into meiosis for both male and female germ cells. Further, the number of PGCs in Faap100 −/− embryos reduced to a quarter of wild type embryos at E11.5, which was similar to the phenotype of Fancd2 K559R/K559R mice with FA pathway-dependent function defect, but was less severe than that in Fancd2 −/− mice lacking both FA pathway-dependent and -independent functions [ 49 ]. In addition, previous studies reported that Fanca −/− mice contained half of the number of PGCs in wild type embryos at E11.5 [ 50 ].…”

Section: Discussionmentioning

confidence: 90%

FAAP100 is required for the resolution of transcription-replication conflicts in primordial germ cells

Xu

¹

,

Yang

²

,

Yu

³

et al. 2023

BMC Biol

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0

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Background The maintenance of genome stability in primordial germ cells (PGCs) is crucial for the faithful transmission of genetic information and the establishment of reproductive reserve. Numerous studies in recent decades have linked the Fanconi anemia (FA) pathway with fertility, particularly PGC development. However, the role of FAAP100, an essential component of the FA core complex, in germ cell development is unexplored. Results We find that FAAP100 plays an essential role in R-loop resolution and replication fork protection to counteract transcription-replication conflicts (TRCs) during mouse PGC proliferation. FAAP100 deletion leads to FA pathway inactivation, increases TRCs as well as cotranscriptional R-loops, and contributes to the collapse of replication forks and the generation of DNA damage. Then, the activated p53 signaling pathway triggers PGC proliferation defects, ultimately resulting in insufficient establishment of reproductive reserve in both sexes of mice. Conclusions Our findings suggest that FAAP100 is required for the resolution of TRCs in PGCs to safeguard their genome stability.

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DNA repair protein FANCD2 has both ubiquitination-dependent and ubiquitination-independent functions during germ cell development

Cited by 13 publications

References 56 publications

Pancancer analysis of the prognostic and immunological role of FANCD2: a potential target for carcinogenesis and survival

Pancancer analysis of the prognostic and immunological role of FANCD2: a potential target for carcinogenesis and survival

Pancancer Analysis of the Prognostic and immunological Role of FANCD2: A Potential Target for Carcinogenesis and Survival

FAAP100 is required for the resolution of transcription-replication conflicts in primordial germ cells

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