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FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

ABSTRACT: Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46902 | GEO | 2013/06/27

SECONDARY ACCESSION(S): PRJNA202990

REPOSITORIES: GEO

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FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells

2013-06-27 | E-GEOD-46902 | biostudies-arrayexpress

Effect of SRSF1 depletion on FANCD2 mRNA and isoform expression and effect of FANCD2 depletion or expression of SRSF1 mutants on splicing

Project description:To investigate the cooperative function of FANCD2/SRSF1 complex in the regulation of R-loops, we performed gene expression, isoform and splicing analysis in Hela cells depleted of SRSF1 or expressing SRSF1 mutants and FA-D2 mutant (FA-D2) and wild type (FA-D2+FANCD2) cells.

2024-02-26 | GSE212471 | GEO

Gene expression profiles of murine Runx1;Runx3 double deficient cKit+Sca1+Lin- hematopoietic stem/progenitor cells

Project description:The RUNX genes encode for transcription factors involved in development and human disease. RUNX1 and RUNX3 are frequently associated with leukemias, yet the basis for their involvement in leukemogenesis is not fully understood. Here we show that Runx1;Runx3 double knockout (DKO) mice exhibited lethal phenotypes due to bone marrow failure and myeloproliferative disorder. These contradictory clinical manifestations are reminiscent of human inherited bone marrow failure syndromes like Fanconi anemia (FA), caused by defective DNA repair. Indeed, Runx1;Runx3 DKO cells showed mitomycin C hypersensitivity, due to impairment of monoubiquitinated-FANCD2 recruitment to DNA damage foci, although FANCD2 monoubiquitination in the FA pathway was unaffected. RUNX1 and RUNX3 interact with FANCD2 independent of CBFβ, suggesting non-transcriptional role for RUNX in DNA repair. These findings suggest that RUNX dysfunction causes DNA repair defect, besides transcriptional misregulation, and promotes development of leukemias and other cancers.

2014-08-26 | GSE51107 | GEO

Crosslinking mass spectrometry (CLMS) analysis of monoubiquitinated FANCD2-FANCI complex

Project description:Vertebrate DNA crosslink repair excises toxic replication-blocking DNA crosslinks. Numerous factors involved in crosslink repair have been identified, and mutations in their corresponding genes cause Fanconi anemia (FA). A key step in crosslink repair is monoubiquitination of the FANCD2-FANCI heterodimer, which then recruits nucleases to remove the DNA lesion. In this study, monoubiquitinated FANCD2-FANCI complex was characterized using crosslinking mass spectrometry in order to provide in sights into the 3D structure of the complex.

2020-03-09 | PXD017020 | Pride

Structure of the Fanconi anaemia monoubiquitin ligase complex

Project description:The Fanconi Anemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks. Genetic inactivation of this pathway impairs development, prevents blood production and promotes cancer. The key molecular step in the FA pathway is the monoubiquitination of a heterodimer of FANCI-FANCD2 by the FA core complex - a megadalton multiprotein E3 ubiquitin ligase. Monoubiquitinated FANCI-FANCD2 then activates a pathway to remove the DNA crosslink. Lack of molecular insight into the FA core complex limits a detailed explanation of how this vital DNA repair pathway functions. Here we reconstituted an active, recombinant FA core complex, and used electron cryo-microscopy (cryo-EM) and mass spectrometry to determine its overall structure. The FA core complex is comprised of a central symmetric dimer of the FANCB and FAAP100 subunits, flanked by two copies of the RING finger protein, FANCL. This acts as a scaffold to assemble the remaining five subunits, resulting in an extended asymmetric structure. The two FANCL subunits are positioned at opposite ends of the complex in an unusual asymmetric arrangement, distinct from other E3 ligases. We propose that each of the two FANCL subunits play unique roles within the complex – one is a structural component while the other monoubiquitinates FANCD2. The cryo-EM structure of the FA core complex, supported by crosslinking mass spectrometry and native mass spectrometry, therefore provides a foundation for a detailed understanding of this fundamental DNA repair pathway.

2019-10-16 | PXD014282 | Pride

TAp63-regulated microRNAs suppress cutaneous squamous cell carcinoma [RNA-seq]

Project description:The goal of this study is to compare the differences in the global mRNA expression of WT and TAp63-/- skin and SCC TAp63 is a p53 family member and potent tumor and metastasis suppressor. Here, we show that TAp63-/- mice exhibit an increased susceptibility to UVR- induced cutaneous squamous cell carcinoma (cuSCC). A human-to-mouse comparison of cuSCC tumors identified miR-30c-2* and miR-497 as underexpressed in TAp63-deficient cuSCC. Reintroduction of these microRNAs significantly inhibited the growth of cuSCC cell lines and tumors. Proteomic profiling of cells expressing either microRNA showed downregulation of cell cycle progression and mitosis associated proteins. A mouse to human and cross- platform comparison of RNA-Seq and proteomics data identified a 7-gene signature, including AURKA, KIF18B, PKMYT1, and ORC1, which were overexpressed in cuSCC. Knockdown of these factors in cuSCC cell lines suppressed tumor cell proliferation and induced apoptosis. Additionally, selective inhibition of AURKA suppressed cuSCC cell proliferation, induced apoptosis, and showed anti-tumor effects in vivo. Finally, treatment with miR-30c-2* or miR-497 microRNA mimics was highly effective in suppressing cuSCC growth in vivo. Our data establishes TAp63 as an essential regulator of novel microRNAs that can be therapeutically targeted for potent suppression of cuSCC.

2020-03-04 | GSE146257 | GEO

Homo sapiens

Project description:FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

| PRJNA202990 | ENA

TAp63-regulated microRNAs suppress cutaneous squamous cell carcinoma

Project description:TAp63 is a transcription factor belonging to the p53 family with important tumor suppressive functions. We show that TAp63-/- mice exhibit an increased susceptibility to UVR-induced cutaneous squamous cell carcinoma (cuSCC). These tumors showed global disruption of miRNA and mRNA expression when compared to tumors arising in wild-type mice. A comparison to similarly sequenced human cuSCC tumors identified miR-30c-2* and miR-497 as being significantly underexpressed in cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and xenografts. Proteomic profiling of cells transfected with either miRNA showed significant downregulation of proteins related to cell cycle progression and mitosis. A cross-platform comparison of the RNAseq and proteomics signatures identified 7 downregulated proteins, which are also frequently overexpressed in both mouse and human cuSCC. Knockdown of AURKA, KIF18B, PKMYT1, and ORC1 in cuSCC cell lines suppressed tumor cell proliferation and induced cell death. Additionally, we found that an investigational, oral, selective inhibitor of AURKA suppressed cuSCC cell growth and induced cell death, and showed anti-tumor effects in vivo. Our data establishes TAp63 as an essential regulator of miRNA expression during skin carcinogenesis and reveals a novel network of miRNAs and mRNAs, which include potential targets for therapeutic intervention.

2020-07-07 | PXD014261 | Pride

Suppression of skin tumorigenesis in CD109-deficient mice

Project description:CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in several types of human cancers, particularly squamous cell carcinomas. We previously reported that CD109-deficient mice exhibit epidermal hyperplasia and chronic skin inflammation. Although we found that CD109 regulates differentiation of keratinocytes in vivo, the function of CD109 in tumorigenesis remains unknown. In this study, we investigated the role of CD109 in skin tumorigenesis using a two-stage carcinogenesis model in CD109-deficient mice with chronic skin inflammation.

2016-09-28 | GSE87390 | GEO

SCAI orchestrates DNA interstrand crosslink repair downstream of FANCI-FANCD2 ubiquitylation

Project description:By covalently linking Watson and Crick strands, DNA interstrand crosslinks (ICLs) are highly toxic lesions that block DNA replication and threaten genome integrity. The Fanconi anemia (FA) pathway orchestrates ICL repair during DNA replication, with ubiquitylated FANCI-FANCD2 (ID2) marking the activation step that triggers incisions on one DNA strand to unhook the ICL. ICL unhooking generates a two-ended double-strand break (DSB) on one of the daughter molecules, while leaving a gap comprising the ICL-adduct on the other. Restoration of the adducted molecule by DNA polymerase zeta-mediated translesion synthesis (TLS) creates a template required for repair of the DSB via homologous recombination (HR), but how these processes are coordinated to ensure faithful ICL repair is not known. Here, we uncover a crucial role for SCAI in promoting ICL repair downstream of ID2 activation. Using Xenopus egg extracts and human cells, we show that SCAI forms a complex with DNA polymerase zeta and localizes to ICLs during DNA replication. SCAI-deficient cells are exquisitely sensitive to ICL-inducing drugs and display principal hallmarks of FA gene inactivation, including broken and radial chromosome accumulation. In the absence of SCAI, DSB intermediates are preferentially re-ligated by illegitimate DNA polymerase theta-dependent microhomology-mediated end-joining (MMEJ). Consistently, the hypersensitivity of SCAI-deficient cells to ICLs can be reverted by suppressing FA pathway activation. Our work establishes SCAI as a critical mediator of ICL resolution via the FA pathway, acting at the interphase of the TLS and HR steps to prevent erroneous repair and chromosomal instability.

2022-02-18 | PXD024280 | Pride

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