Update of the human and mouse Fanconi anemia genes

Dong, Hongbin; Nebert, Daniel W.; Bruford, Elspeth A.; Thompson, David C.; Joenje, Hans; Vasiliou, Vasilis

doi:10.1186/s40246-015-0054-y

Cited by 137 publications

(115 citation statements)

References 91 publications

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“…The fact that Rfwd3 -/-mice fail to show a recognizable pattern of phenotypical anomalies that resemble those in FA patients is compatible with this view, as it is mirrored in other FA KO mouse models (41)(42)(43). Nonetheless, subfertility and embryonic lethality are features frequently seen in other FA mouse models (41). No matter whether Rfwd3 -/-mice are completely sterile or not, it is a trait in which they resemble either recently reported Fancp -/-mice or other FA mouse models (41)(42)(43).…”

Section: Discussionsupporting

confidence: 59%

Section: Discussionsupporting

confidence: 57%

“…Nonetheless, subfertility and embryonic lethality are features frequently seen in other FA mouse models (41). No matter whether Rfwd3 -/-mice are completely sterile or not, it is a trait in which they resemble either recently reported Fancp -/-mice or other FA mouse models (41)(42)(43). Rfwd3 -/-mice, or their cells, may serve for studies of attrition of hematopoietic stem cells in FA, for transplantation studies, for sensitivity testing of aldehydes and oxygen, and for drug screens.…”

Section: Discussionmentioning

confidence: 98%

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Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

177

171

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The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G 2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.

show abstract

Section: Discussionsupporting

confidence: 59%

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

177

171

View full text Add to dashboard Cite

show abstract

“…The major pathway of ICL repair is coupled to DNA replication and involves the coordinated action of many DNA repair proteins including the Fanconi anemia (FA) pathway proteins. Mutations in any of the 21 currently known FA genes give rise to Fanconi anemia (FA), a cancer susceptibility disorder characterized by cellular sensitivity to ICL‐inducing agents (Kottemann & Smogorzewska, 2013; Dong et al , 2015). Using a Xenopus egg extract‐based assay, we and others have recently elucidated a molecular mechanism of replication‐coupled ICL repair (Fig EV1; Räschle et al , 2008).…”

Section: Introductionmentioning

confidence: 99%

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

et al. 2017

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XPF‐ERCC1 is a structure‐specific endonuclease pivotal for several DNA repair pathways and, when mutated, can cause multiple diseases. Although the disease‐specific mutations are thought to affect different DNA repair pathways, the molecular basis for this is unknown. Here we examine the function of XPF‐ERCC1 in DNA interstrand crosslink (ICL) repair. We used Xenopus egg extracts to measure both ICL and nucleotide excision repair, and we identified mutations that are specifically defective in ICL repair. One of these separation‐of‐function mutations resides in the helicase‐like domain of XPF and disrupts binding to SLX4 and recruitment to the ICL. A small deletion in the same domain supports recruitment of XPF to the ICL, but inhibited the unhooking incisions most likely by disrupting a second, transient interaction with SLX4. Finally, mutation of residues in the nuclease domain did not affect localization of XPF‐ERCC1 to the ICL but did prevent incisions on the ICL substrate. Our data support a model in which the ICL repair‐specific function of XPF‐ERCC1 is dependent on recruitment, positioning and substrate recognition.

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“…11 Fanconi anemia is an inherited disease that is characterized by bone marrow failure and a strong predisposition to cancer. 12 At least 19 genes have been implicated in the FA pathway, 13 which is thought to coordinate at least 3 downstream repair processes; including homologous recombination (HR), nucleotide excision repair (NER), and translesion DNA synthesis (TLS). In response to crosslinking DNA damage, 8 FA proteins (FANCA, B, C, E, F, G, L, and M) form the FA core complex at the site of DNA damage, promoting ubiquitination of the FANCD2-FANCI complex.…”

Section: Introductionmentioning

confidence: 99%

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

et al. 2016

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Acetaldehyde, a primary metabolite of alcohol, forms DNA adducts and disrupts the DNA replication process, causing genomic instability, a hallmark of cancer. Indeed, chronic alcohol consumption accounts for approximately 3.6% of all cancers worldwide. However, how the adducts are prevented and repaired after acetaldehyde exposure is not well understood. In this report, we used the fission yeast Schizosaccharomyces pombe as a model organism to comprehensively understand the genetic controls of DNA damage avoidance in response to acetaldehyde. We demonstrate that Atd1 functions as a major acetaldehyde detoxification enzyme that prevents accumulation of Rad52-DNA repair foci, while Atd2 and Atd3 have minor roles in acetaldehyde detoxification. We found that acetaldehyde causes DNA damage at the replication fork and activates the cell cycle checkpoint to coordinate cell cycle arrest with DNA repair. Our investigation suggests that acetaldehyde-mediated DNA adducts include interstrand-crosslinks and DNA-protein crosslinks. We also demonstrate that acetaldehyde activates multiple DNA repair pathways. Nucleotide excision repair and homologous recombination, which are both epistatically linked to the Fanconi anemia pathway, have major roles in acetaldehyde tolerance, while base excision repair and translesion synthesis also contribute to the prevention of acetaldehyde-dependent genomic instability. We also show the involvement of Wss1-related metalloproteases, Wss1 and Wss2, in acetaldehyde tolerance. These results indicate that acetaldehyde causes cellular stresses that require cells to coordinate multiple cellular processes in order to prevent genomic instability. Considering that acetaldehyde is a human carcinogen, our genetic studies serve as a guiding investigation into the mechanisms of acetaldehyde-dependent genomic instability and carcinogenesis.

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Update of the human and mouse Fanconi anemia genes

Cited by 137 publications

References 91 publications

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

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