The Fanconi anemia pathway requires FAA phosphorylation and FAA/FAC nuclear accumulation (original) (raw)

Function of the Fanconi anemia pathway in Fanconi anemia complementation group F and D1 cells

Experimental Hematology, 2001

Objective. Fanconi anemia (FA) is a human autosomal-recessive cancer susceptibility disorder characterized by multiple congenital abnormalities, progressive bone marrow failure, and cellular sensitivity to mitomycin C (MMC). FA has at least eight complementation groups (A, B, C, D1, D2, E, F, G), and six of the FA genes have been cloned. Several FA proteins, including FANCA, FANCC, FANCF, and FANCG, interact in a nuclear complex, and this complex is required for the activation (monoubiquitination) of the downstream FANCD2 protein. Activation of FANCD2 results in the assembly of FANCD2/BRCA1 foci. The aim of this study was to analyze the FA pathway in several FA patient-derived cell lines.

Gene-specific selection against experimental fanconi anemia gene inactivation in human cancer

Cancer Biology & Therapy, 2007

The Fanconi anemia (FA) gene family comprises at least 12 genes interacting in a common pathway involved in DNA repair. To gain insight into the role of FA gene inactivation occurring in tumors among the general population, we endogenously targeted in cancer cells four FA genes that act at different stages of the FA pathway. After successful mono-allelic deletion of all genes, the sequential homozygous deletion was achieved only for FANCC and FANCG, acting upstream, but not for BRCA2 or FANCD2, acting downstream in the FA pathway. Targeting of the second allele in in BRCA2 and FANCD2 heterozygote clones resulted in redeletion exclusively of the already defective allele in multiple instances (13x concerning BRCA2, 25x concerning FANCD2), strongly suggesting a detrimental phenotype. Unlike complete FANCD2 disruption, the mere reduction of FANCD2 protein levels had no discernible effect. In addition, we confirmed that human cancer cells harboring the Seckel ATR mutation display impaired FANCD2 monoubiquitination and FANCD2 nuclear focus formation, as well as an increased sensitivity to DNA interstrand-crosslinking agents. Nevertheless, these cells were viable, indicating an ATR-independent function of FANCD2, distinct from its major known functions, to be responsible for the detrimental effects of FANCD2 loss. In conclusion, we established the downstream FA genes FANCD2 and BRCA2 to represent particularly vulnerable parts of the FA pathway, providing direct evidence for the paradoxical assumption that their inactivation could be predominantly selected against in cancer cells. This would explain why certain FA gene defects, despite an apparent selection for FA pathway inactivation in cancer, are rarely observed in tumors among the general population.

Fanconi Anemia Signaling and Cancer

Trends in cancer, 2017

The extremely high cancer incidence associated with patients suffering from a rare human genetic disease, Fanconi anemia (FA), demonstrates the importance of FA genes. Over the course of human tumor development, FA genes perform critical tumor-suppression roles. In doing so, FA provides researchers with a unique genetic model system to study cancer etiology. Here, we review how aberrant function of the 22 FA genes and their signaling network contributes to malignancy. From this perspective, we will also discuss how the knowledge discovered from FA research serves basic and translational cancer research.

Identification of the Fanconi anemia complementation group I gene, FANCI

Analytical Cellular …, 2007

To identify the gene underlying Fanconi anemia (FA) complementation group I we studied informative FA-I families by a genome-wide linkage analysis, which resulted in 4 candidate regions together encompassing 351 genes. Candidates were selected via bioinformatics and data mining on the basis of their resemblance to other FA genes/proteins acting in the FA pathway, such as: degree of evolutionary conservation, presence of nuclear localization signals and pattern of tissue-dependent expression. We found a candidate, KIAA1794 on chromosome 15q25-26, to be mutated in 8 affected individuals previously assigned to complementation group I. Western blots of endogenous FANCI indicated that functionally active KIAA1794 protein is lacking in FA-I individuals. Knock-down of KIAA1794 expression by siRNA in HeLa cells caused excessive chromosomal breakage induced by mitomycin C, a hallmark of FA cells. Furthermore, phenotypic reversion of a patient-derived cell line was associated with a secondary genetic alteration at the KIAA1794 locus. These data add up to two conclusions. First, KIAA1794 is a FA gene. Second, this gene is identical to FANCI, since the patient cell lines found mutated in this study included the reference cell line for group I, EUFA592.

Formation in Fanconi Anemia Complementation Group D2 (Fancd2) Knockout Mice

2000

Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure and an increased susceptibility to cancer. FA is genetically heteroge- neous, consisting of at least 11 complementation groups, FA-A through L, including FA-D1 (BRCA2 )a nd D2. We have previously reported an increased incidence of epithelial tumors in Fancd2 knockout mice. To further investigate the role