Severe Fanconi Anemia phenotypes in Fancd2 depletion mice

Qiao, Yi; Xie, Hui; Zhong, Yixinhe; Li, Dongbo; Ke, Xu; Ying, Hua‐Zhong; Yu, Bing; Zhang, Tingting

doi:10.1016/j.bbrc.2019.04.201

Cited by 10 publications

(12 citation statements)

References 23 publications

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“…In this new model generated by Yang et al. (57), the deletion of exon 5 of Fancd2 results in more severe phenotypes than the model generated by Houghtaling et al. which had deletion of exons 26–27 of Fancd2 (21).…”

Section: Discussionmentioning

confidence: 88%

“…(21). During the review process of this manuscript, the generation of a Fancd2 depletion mice by CRISPR-Cas9 was reported (57). In this new model generated by Yang et al.…”

Section: Discussionmentioning

confidence: 99%

“…Yang et al. report higher rates of embryonic and postnatal lethality, higher incidence of microphthalmia and more severe hypogonadism and only aberrant tubules with total absence of germ cells (57). Thus, we can conclude that the Fanci knockout mice have a more severe phenotype than the Fancd2 knockout mice generated by Houghtaling et al.…”

Section: Discussionmentioning

confidence: 99%

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A Fanci knockout mouse model reveals common and distinct functions for FANCI and FANCD2

Dubois

Guitton-Sert

Béliveau

et al. 2019

Nucleic Acids Research

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Fanconi Anemia (FA) clinical phenotypes are heterogenous and rely on a mutation in one of the 22 FANC genes (FANCA-W) involved in a common interstrand DNA crosslink-repair pathway. A critical step in the activation of FA pathway is the monoubiquitination of FANCD2 and its binding partner FANCI. To better address the clinical phenotype associated with FANCI and the epistatic relationship with FANCD2, we created the first conditional inactivation model for FANCI in mouse. Fanci −/− mice displayed typical FA features such as delayed development in utero, microphtalmia, cellular sensitivity to mitomycin C, occasional limb abnormalities and hematological deficiencies. Interestingly, the deletion of Fanci leads to a strong meiotic phenotype and severe hypogonadism. FANCI was localized in spermatocytes and spermatids and in the nucleus of oocytes. Both FANCI and FANCD2 proteins co-localized with RPA along meiotic chromosomes, albeit at different levels. Consistent with a role in meiotic recombination, FANCI interacted with RAD51 and stimulated D-loop formation, unlike FANCD2. The double knockout Fanci−/− Fancd2−/− also showed epistatic relationship for hematological defects while being not epistatic with respect to generating viable mice in crosses of double heterozygotes. Collectively, this study highlights common and distinct functions of FANCI and FANCD2 during mouse development, meiotic recombination and hematopoiesis.

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Section: Discussionmentioning

confidence: 88%

“…(21). During the review process of this manuscript, the generation of a Fancd2 depletion mice by CRISPR-Cas9 was reported (57). In this new model generated by Yang et al.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Fanci knockout mouse model reveals common and distinct functions for FANCI and FANCD2

Dubois

Guitton-Sert

Béliveau

et al. 2019

Nucleic Acids Research

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“…These studies have linked Fancd2 to organismal viability, germ cell function, and cancer predisposition in the absence of DNA damage. Further, mirroring findings in human cells, Fancd2 mutants in mice, zebrafish, Caenorhabditis elegans , and Drosophila , all compromise organismal viability in response to DNA damaging ICL or DSB agents ( Houghtaling et al 2003 ; Marek and Bale 2006 ; Lee et al 2007 , 2010 ; Vinciguerra et al 2010 ; Bretscher and Fox 2016 ; Ramanagoudr-Bhojappa et al 2018 ; Yang et al 2019 ; Germoglio et al 2020 ; Clay et al 2021 ). The conservation of critical FA proteins across various species emphasizes the importance of the pathway in maintaining genomic stability.…”

Section: Introductionmentioning

confidence: 64%

“…Instead of point mutations, previous studies of Fancd2 in systems such as mice, zebrafish, C. elegans , and Drosophila have focused on complete gene knockout or knockdown. In mice, molecular null Fancd2 heterozygous animals yield homozygotes at reduced Mendelian frequencies in specific genetic backgrounds ( Houghtaling et al 2003 ; Parmar et al 2010 ; Yang et al 2019 ), and a C. elegans deletion allele has egg-laying defects ( Lee et al 2007 , 2010 ). Our findings here with reduced Mendelian frequencies of homozygotes in Drosophila for our 2 CRISPR point mutant alleles in conserved residues, as well as the deletion allele, mirror those previous findings with whole gene knockouts .…”

Section: Discussionmentioning

confidence: 99%

Conserved function ofDrosophilaFancd2 monoubiquitination in response to double-strand DNA breaks

Clay

Jezuit

Montague

et al. 2022

G3 Genes|Genomes|Genetics

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Fanconi anemia genes play key roles in metazoan DNA damage responses, and human FA mutations cause numerous disease phenotypes. In human cells, activating monoubiquitination of the Fanconi anemia protein Fancd2 occurs following diverse DNA damage stimuli. Monoubiquitinated Fancd2 forms nuclear foci to recruit additional repair factors. Fancd2 animal models to date have focused on molecular nulls or whole gene knockdown, leaving the specific in vivo role of monoubiquitination unclear. Using a point mutant in a conserved residue, we recently linked Drosophila Fancd2 monoubiquitination to a mitosis-specific DNA double-strand break response. In this context, we used CRISPR/Cas9 to generate the first animal model of an endogenous mutation in the conserved monoubiquitination site (fancd2K595R). Here, we expand upon our characterization of fancd2K595R. We also introduce and characterize additional Drosophila tools to study fancd2, including new mutant alleles and GFP-tagged rescue transgenes. Using these new reagents, we show the impact of Drosophila Fancd2 on organismal and cell viability, as well as on repair protein localization, in the presence or absence of double-strand breaks. These findings expand our understanding of Fanconi anemia gene function in vivo and provide useful reagents for DNA repair research.

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Fanconi anemia and the underlying causes of genomic instability

Rageul

Kim

2020

Environ and Mol Mutagen

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Fanconi anemia (FA) is a rare genetic disorder, characterized by birth defects, progressive bone marrow failure, and a predisposition to cancer. This devastating disease is caused by germline mutations in any one of the 22 known FA genes, where the gene products are primarily responsible for the resolution of DNA interstrand cross‐links (ICLs), a type of DNA damage generally formed by cytotoxic chemotherapeutic agents. However, the identity of endogenous mutagens that generate DNA ICLs remains largely elusive. In addition, whether DNA ICLs are indeed the primary cause behind FA phenotypes is still a matter of debate. Recent genetic studies suggest that naturally occurring reactive aldehydes are a primary source of DNA damage in hematopoietic stem cells, implicating that they could play a role in genome instability and FA. Emerging lines of evidence indicate that the FA pathway constitutes a general surveillance mechanism for the genome by protecting against a variety of DNA replication stresses. Therefore, understanding the DNA repair signaling that is regulated by the FA pathway, and the types of DNA lesions underlying the FA pathophysiology is crucial for the treatment of FA and FA‐associated cancers. Here, we review recent advances in our understanding of the relationship between reactive aldehydes, bone marrow dysfunction, and FA biology in the context of signaling pathways triggered during FA‐mediated DNA repair and maintenance of the genomic integrity. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc.

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Severe Fanconi Anemia phenotypes in Fancd2 depletion mice

Cited by 10 publications

References 23 publications

A Fanci knockout mouse model reveals common and distinct functions for FANCI and FANCD2

A Fanci knockout mouse model reveals common and distinct functions for FANCI and FANCD2

Conserved function ofDrosophilaFancd2 monoubiquitination in response to double-strand DNA breaks

Fanconi anemia and the underlying causes of genomic instability

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