Monoubiquitination by the human Fanconi Anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays

We report that monoubiquitination does not promote any specific exogenous protein:protein interactions, but instead stabilizes FANCI:FANCD2 heterodimers on dsDNA. This clamping requires monoubiquitination of only the FANCD2 subunit. We further show that purified monoubiquitinated FANCI:FANCD2 forms filament-like arrays on long dsDNA using electron microscopy. Our results reveal how monoubiquitinated FANCI:FANCD2, defective in many cancer types and all cases of FA, is activated upon DNA binding.
Source: eLife - Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

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ConclusionsHeterozygous pathogenic variants inFANCN/PALB2 and possiblyFANCJ/BRIP1 may account for 1 –2% of familial non-BRCA1/2 breast cancer cases and 0.5–1% of unselected cases. Genetic counseling and testing may be suggested for unaffected relatives.
Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
DNA interstrand cross-links (ICLs) are a form of DNA damage that requires the interplay of a number of repair proteins including those of the Fanconi anemia (FA) and the homologous recombination (HR) pathways. Pathogenic variants in the essential gene BRCA2/FANCD1, when monoallelic, predispose to breast and ovarian cancer, and when biallelic, result in a severe subtype of Fanconi anemia. BRCA2 function in the FA pathway is attributed to its role as a mediator of the RAD51 recombinase in HR repair of programmed DNA double-strand breaks (DSB). BRCA2 and RAD51 functions are also required to protect stalled replication forks f...
Source: Genes and Development - Category: Genetics & Stem Cells Authors: Tags: Research Papers Source Type: research
In conclusion, FOXM1 and FANCD2 can be used as prognostic factors that are associated with high risk of recurrence and with anticancer drug resistance properties in NMIBC patients.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
In conclusion, the combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18 FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response. IMPLICATIONS FOR PRACTICE: The BROCADE studies suggest that patients with BRCA mutation benefit from addition of the poly(ADP-ribose) polymerase inhibitor veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in ima...
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Oncologist Source Type: research
Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of disorders characterized by defective hematopoiesis, impaired stem cell function, and cancer susceptibility. Diagnosis of IBMFS presents a major challenge due to the large variety of associated phenotypes, and novel, clinically relevant biomarkers are urgently needed. Our study identified nuclear interaction partner of ALK (NIPA) as an IBMFS gene, as it is significantly downregulated in a distinct subset of myelodysplastic syndrome–type (MDS-type) refractory cytopenia in children. Mechanistically, we showed that NIPA is major player in the F...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
by Sarmi Nath, Ganesh Nagaraju FANCJ helicase mutations are known to cause hereditary breast and ovarian cancers as well as bone marrow failure syndrome Fanconi anemia. FANCJ plays an important role in the repair of DNA inter-strand crosslinks and DNA double-strand breaks (DSBs) by homologous recombination (HR). Nonetheless, th e molecular mechanism by which FANCJ controls HR mediated DSB repair is obscure. Here, we show that FANCJ promotes DNA end resection by recruiting CtIP to the sites of DSBs. This recruitment of CtIP is dependent on FANCJ K1249 acetylation. Notably, FANCJ acetylation is dependent on FANCJ S990 phosp...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research
We examined the subcellular localization of FANCD2 in primary OSE cells from consenting patients with ovarian cancer or a normal ovary. Ovarian tissue microarray was stained with anti-FANCD2 antibody by immunohistochemistry and the correlation of FANCD2 localization with patient outcomes was assessed. FANCD2 binding partners were identified by immunoprecipitation of cytoplasmic FANCD2. RESULTS: Nuclear and cytoplasmic localization of FANCD2 was observed in OSEs from both normal and ovarian cancer patients. Patients with cytoplasmic localization of FANCD2 (cFANCD2) experienced significantly longer median survival time (...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Mu-Yan Cai, Connor E. Dunn, Wenxu Chen, Bose S. Kochupurakkal, Huy Nguyen, Lisa A. Moreau, Geoffrey I. Shapiro, Kalindi Parmar, David Kozono, Alan D. D’AndreaSummaryCells deficient in ataxia telangiectasia mutated (ATM) are hypersensitive to ionizing radiation and other anti-cancer agents that induce double-strand DNA breaks. ATM inhibitors may therefore sensitize cancer cells to these agents. Some cancers may also have underlying genetic defects predisposing them to an ATM inhibitor monotherapy response. We have conducted a genome-w...
Source: Cell Reports - Category: Cytology Source Type: research
M. Wells Amir Abdollahi Radiation-induced normal tissue toxicity often limits the curative treatment of cancer. Moreover, normal tissue relative biological effectiveness data for high-linear energy transfer particles are urgently needed. We propose a strategy based on transcriptome analysis of patient-derived human intestinal organoids (HIO) to determine molecular surrogates for radioresponse of gastrointestinal (GI) organs at risk in a personalized manner. HIO were generated from induced pluripotent stem cells (iPSC), which were derived from skin biopsies of three patients, including two patients with FANCA deficie...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Abstract Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects of TTFields on cancer cells; however, TTFields was shown to not only reduce the rejoining of radiation-induced DNA double-strand breaks (DSBs), but to also induce DNA DSBs. The mechanism(s) by which TTFields generates DNA DSBs is related to the generation of replication stress including reduced expression of the DNA replication complex genes MCM6 and MCM1...
Source: Translational Research : the journal of laboratory and clinical medicine - Category: Laboratory Medicine Authors: Tags: Transl Res Source Type: research
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