Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia

ConclusionThese results underscore the consequences of defects in the DNA cross ‐link repair mechanism and indicate that accumulating diverse mutations from individual parent cells may make it difficult to anticipate the longitudinal clinical behavior of emerging disease states in an individual with FA.
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: ORIGINAL ARTICLE Source Type: research

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AbstractGenome editing of hematopoietic stem cells (HSCs) represents a therapeutic option for a number of hematological genetic diseases, as HSCs have the potential for self ‐renewal potential and differentiation into all blood cell lineages. This review presents advances of genome editing in HSCs utilizing adenovirus vectors as delivery vehicles. We focus on capsid‐modified, helper‐dependent adenovirus vectors that are devoid of all viral genes and therefore exhi bit an improved safety profile. We discuss HSC genome engineering for several inherited disorders and infectious diseases including hemoglobinopathies, Fan...
Source: FEBS Letters - Category: Biochemistry Authors: Tags: REVIEW 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
by Edwige B. Garcin, St éphanie Gon, Meghan R. Sullivan, Gregory J. Brunette, Anne De Cian, Jean-Paul Concordet, Carine Giovannangeli, Wilhelm G. Dirks, Sonja Eberth, Kara A. Bernstein, Rohit Prakash, Maria Jasin, Mauro Modesti Deficiency in several of the classical human RAD51 paralogs [RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3] is associated with cancer predisposition and Fanconi anemia. To investigate their functions, isogenic disruption mutants for each were generated in non-transformed MCF10A mammary epithelial cells and in transformed U2OS and HEK293 cells. In U2OS and HEK293 cells, viable ablated clones were r...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research
In this study, we show that CASIN, a selective inhibitor of cell division cycle 42 (Cdc42) GTPase, inhibited proliferation and survival of melphalan/bortezomib-resistant MM cells more profoundly than that of the sensitive cells. Furthermore, CASIN was more potent than melphalan/bortezomib in inhibiting melphalan/bortezomib-resistant cells. In addition, CASIN sensitized melphalan/bortezomib-resistant cells to this drug combination. Mechanistically, Cdc42 activity was higher in melphalan/bortezomib-resistant cells than that in the sensitive cells. CASIN inhibited mono-ubiquitination of Fanconi anemia (FA) complementation gro...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Abstract Fanconi anemia, an inherited bone marrow failure syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with Fanconi anemia from the Israeli inherited bone marrow failure registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 (range 0.1-49) years; sixty-three percent were offspring of consanguineous parents. One-hundred...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
AbstractPremature ovarian insufficiency (POI) is a major cause of reduced female fertility and affects approximately 1% women under 40  years of age. Recent advances emphasize the genetic heterogeneity of POI. Fanconi anemia (FA) genes, traditionally known for their essential roles in DNA repair and cytogenetic instability, have been demonstrated to be involved in meiosis and germ cell development. Here, we conducted whole-exome s equencing (WES) in 50 Han Chinese female patients with POI. Rare missense variants were identified inFANCA (Fanconi anemia complementation group A): c.1772G  >  A (p.R591Q) ...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research
Torres-Ruiz R, Surrallés J, Bueren JA, Río P Abstract Non-homologous end-joining (NHEJ) is the preferred mechanism used by hematopoietic stem cells (HSCs) to repair double-stranded DNA breaks and is particularly increased in cells deficient in the Fanconi anemia (FA) pathway. Here, we show feasible correction of compromised functional phenotypes in hematopoietic cells from multiple FA complementation groups, including FA-A, FA-C, FA-D1, and FA-D2. NHEJ-mediated repair of targeted CRISPR-Cas9-induced DNA breaks generated compensatory insertions and deletions that restore the coding frame of the mutat...
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research
VOLUME 287 (2012) PAGES 3366–3380The comet sub-panels in Fig. S4 were erroneously copied during figure assembly. This error has now been corrected using the original files. These changes do not affect the results or conclusions of this work. The authors sincerely apologize for the error.jbc;294/35/13198/FU1F1FU1
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Additions and Corrections Source Type: research
Conditions:   ARID1A Gene Mutation;   ATM Gene Mutation;   ATR Gene Mutation;   Bile Duct Adenocarcinoma;   BRCA1 Gene Mutation;   BRCA2 Gene Mutation;   BRIP1 Gene Mutation;   CHEK2 Gene Mutation;   EMSY Gene Mutation;   Fanconi Anemia Complementation Group Gene Mutation;   Metast atic Bile Duct Carcinoma;   MRE11 Gene Mutation;   NBN Gene Mutation;   PALB2 Gene Mutation;   PTEN Gene Deletion;   RAD51...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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