SnapShot: Fanconi Anemia and Associated Proteins

Wang, Anderson T.; Smogorzewska, Agata

doi:10.1016/j.cell.2014.12.031

Cited by 143 publications

(153 citation statements)

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“…This Darwinian premise should have prevented the translation of polygenic inheritance from an inbred species, in which the multiple genes governing the phenotype are analyzed in numerous, albeit clonal, organisms and their crosses, to outbred populations, in which, by definition, the phenotype of each individual is unique and controlled by a unique genotype (regardless of the number of loci involved). Even the rarest Mendelian disorders, such as Fanconi anemia, display very high levels of genetic and phenotypic heterogeneity (140). How could this heterogeneity not hold true for infectious diseases as well?…”

Section: Common Variants and Infectious Diseasesmentioning

confidence: 99%

Human genetic basis of interindividual variability in the course of infection

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

160

111

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The key problem in human infectious diseases was posed at the turn of the 20th century: their pathogenesis. For almost any given virus, bacterium, fungus, or parasite, life-threatening clinical disease develops in only a small minority of infected individuals. Solving this infection enigma is important clinically, for diagnosis, prognosis, prevention, and treatment. Some microbes will inevitably remain refractory to, or escape vaccination, or chemotherapy, or both. The solution also is important biologically, because the emergence and evolution of eukaryotes alongside more rapidly evolving prokaryotes, archaea, and viruses posed immunological challenges of an ecological and evolutionary nature. We need to study these challenges in natural, as opposed to experimental, conditions, and also at the molecular and cellular levels. According to the human genetic theory of infectious diseases, inborn variants underlie life-threatening infectious diseases. Here I review the history of the field of human genetics of infectious diseases from the turn of the 19th century to the second half of the 20th century. This paper thus sets the scene, providing the background information required to understand and appreciate the more recently described monogenic forms of resistance or predisposition to specific infections discussed in a second paper in this issue.

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Section: Common Variants and Infectious Diseasesmentioning

confidence: 99%

Human genetic basis of interindividual variability in the course of infection

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

160

111

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“…Mutations in at least 19 FANC genes have been identified in patients with FA, while FANCD2/FANCI-associated nuclease 1 (FAN1) is the only known gene that is found to be inactivated in KIN patients (Zhou et al 2012;Rickman et al 2015;Wang and Smogorzewska 2015). Proteins encoded by the FANC genes (FANCA to FANCT) are directly involved in the repair of the ICL lesions during DNA replication (for review, see Kottemann and Smogorzewska 2013;Walden and Deans 2014;Wang and Smogorzewska 2015).…”

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confidence: 99%

“…Proteins encoded by the FANC genes (FANCA to FANCT) are directly involved in the repair of the ICL lesions during DNA replication (for review, see Kottemann and Smogorzewska 2013;Walden and Deans 2014;Wang and Smogorzewska 2015). Eight of these proteins form the FA core complex, which is necessary for ubiquitination of the FANCD2-FANCI (ID2) complex.…”

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confidence: 99%

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

et al. 2016

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Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitinbinding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5 ′ -3 ′ exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit + cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency.

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“…Fanconi anemia (FA) is a multigenic disease marked by developmental abnormalities, progressive bone marrow failure, and cancer predisposition (Wang and Smogorzewska 2015). Despite excellent progress in identifying FA proteins and their functions, much remains to be learned about how the activities of these proteins are regulated (Kim and D'Andrea 2012;Kottemann and Smogorzewska 2013;Longerich et al 2014;Wang and Smogorzewska 2015).…”

mentioning

confidence: 99%

“…Despite excellent progress in identifying FA proteins and their functions, much remains to be learned about how the activities of these proteins are regulated (Kim and D'Andrea 2012;Kottemann and Smogorzewska 2013;Longerich et al 2014;Wang and Smogorzewska 2015). FANCM is one of the highly conserved core FA proteins (Meetei et al 2005;Mosedale et al 2005).…”

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confidence: 99%

Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1

et al. 2016

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We identified Mte1 (Mph1-associated telomere maintenance protein 1) as a multifunctional regulator of Saccharomyces cerevisiae Mph1, a member of the FANCM family of DNA motor proteins important for DNA replication fork repair and crossover suppression during homologous recombination. We show that Mte1 interacts with Mph1 and DNA species that resemble a DNA replication fork and the D loop formed during recombination. Biochemically, Mte1 stimulates Mph1-mediated DNA replication fork regression and branch migration in a model substrate. Consistent with this activity, genetic analysis reveals that Mte1 functions with Mph1 and the associated MHF complex in replication fork repair. Surprisingly, Mte1 antagonizes the D-loop-dissociative activity of Mph1-MHF and exerts a procrossover role in mitotic recombination. We further show that the influence of Mte1 on Mph1 activities requires its binding to Mph1 and DNA. Thus, Mte1 differentially regulates Mph1 activities to achieve distinct outcomes in recombination and replication fork repair.

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SnapShot: Fanconi Anemia and Associated Proteins

Cited by 143 publications

References 0 publications

Human genetic basis of interindividual variability in the course of infection

Human genetic basis of interindividual variability in the course of infection

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1

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