Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fanconi anemia (FA) is caused by mutations in 13 Fanc genes and renders cells hypersensitive to DNA interstrand cross-linking (ICL) agents. A central event in the FA pathway is mono-ubiquitylation of the FANCI-FANCD2 (ID) protein complex. Here, we characterize a previously unrecognized nuclease, Fanconi anemia-associated nuclease 1 (FAN1), that promotes ICL repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on mono-ubiquitylation of the ID complex. Thus, the mono-ubiquitylated ID complex recruits the downstream repair protein FAN1 and facilitates the repair of DNA interstrand cross-links.
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PMID:FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. 2067 Aug 86

Fanconi anemia (FA) is a genomic instability disorder characterized by bone marrow failure and cancer predisposition. FA is caused by mutations in any one of several genes that encode proteins cooperating in a repair pathway and is required for cellular resistance to DNA crosslinking agents. Recent studies suggest that the FA pathway may also play a role in mitosis, since FANCD2 and FANCI, the 2 key FA proteins, are localized to the extremities of ultrafine DNA bridges (UFBs), which link sister chromatids during cell division. However, whether FA proteins regulate cell division remains unclear. Here we have shown that FA pathway-deficient cells display an increased number of UFBs compared with FA pathway-proficient cells. The UFBs were coated by BLM (the RecQ helicase mutated in Bloom syndrome) in early mitosis. In contrast, the FA protein FANCM was recruited to the UFBs at a later stage. The increased number of bridges in FA pathway-deficient cells correlated with a higher rate of cytokinesis failure resulting in binucleated cells. Binucleated cells were also detectable in primary murine FA pathway-deficient hematopoietic stem cells (HSCs) and bone marrow stromal cells from human patients with FA. Based on these observations, we suggest that cytokinesis failure followed by apoptosis may contribute to bone marrow failure in patients with FA.
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PMID:Cytokinesis failure occurs in Fanconi anemia pathway-deficient murine and human bone marrow hematopoietic cells. 2118 85

The Fanconi anemia (FA) network is important for the repair of interstrand DNA cross-links. A key event in FA pathway activation is the monoubiquitylation of the FA complementation group I (FANCI)-FANCD2 (ID) complex by FA complementation group L (FANCL), an E3 ubiquitin ligase. In this study, we show that RAD18, another DNA damage-activated E3 ubiquitin ligase, also participates in ID complex activation by ubiquitylating proliferating cell nuclear antigen (PCNA) on Lys164, an event required for the recruitment of FANCL to chromatin. We also found that monoubiquitylated PCNA stimulates FANCL-catalyzed FANCD2 and FANCI monoubiquitylation. Collectively, these experiments identify RAD18-mediated PCNA monoubiquitination as a central hub for the mobilization of the FA pathway by promoting FANCL-mediated FANCD2 monoubiquitylation.
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PMID:RAD18-mediated ubiquitination of PCNA activates the Fanconi anemia DNA repair network. 2093 99

Fanconi anemia (FA) is a rare familial genome instability syndrome caused by mutations in FA genes that results in defective DNA crosslink repair. Activation of the FA pathway requires the FA core ubiquitin ligase complex-dependent monoubiquitination of 2 interacting FA proteins, FANCI and FANCD2. Although loss of either FANCI or FANCD2 is known to prevent monoubiquitination of its respective partner, it is unclear whether FANCI has any additional domains that may be important in promoting DNA repair, independent of its monoubiquitination. Here, we focus on an FA-I patient-derived FANCI mutant protein, R1299X (deletion of 30 residues from its C-terminus), to characterize important structural region(s) in FANCI that is required to activate the FA pathway. We show that, within this short 30 amino acid stretch contains 2 separable functional signatures, a nuclear localization signal and a putative EDGE motif, that is critical for the ability of FANCI to properly monoubiquitinate FANCD2 and promote DNA crosslink resistance. Our study enable us to conclude that, although proper nuclear localization of FANCI is crucial for robust FANCD2 monoubiquitination, the putative FANCI EDGE motif is important for DNA crosslink repair.
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PMID:Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair. 2097 53

Fanconi anemia (FA) is an inherited disease characterized by bone marrow failure, increased cancer risk and hypersensitivity to DNA cross-linking agents, implying a role for this pathway in the maintenance of genomic stability. The central player of the FA pathway is the multi-subunit E3 ubiquitin ligase complex activated through a replication- and DNA damage-dependent mechanism. A consequence of the activation of the complex is the monoubiquitylation of FANCD2 and FANCI, late term effectors in the maintenance of genome integrity. The details regarding the coordination of the FA-dependent response and the DNA replication process are still mostly unknown. We found, by yeast two-hybrid assay and co-immunoprecipitation in human cells, that the core complex subunit FANCF physically interacts with PSF2, a member of the GINS complex essential for both the initiation and elongation steps of DNA replication. In HeLa cells depleted for PSF2, we observed a decreased binding to chromatin of the FA core complex, suggesting that the GINS complex may have a role in either loading or stabilizing the FA core complex onto chromatin. Consistently, GINS and core complex bind chromatin contemporarily upon origin firing and PSF2 depletion sensitizes cells to DNA cross-linking agents. However, depletion of PSF2 is not sufficient to reduce monoubiquitylation of FANCD2 or its localization to nuclear foci following DNA damage. Our results suggest a novel crosstalk between DNA replication and the FA pathway.
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PMID:Physical and functional crosstalk between Fanconi anemia core components and the GINS replication complex. 2110 93

Fanconi anemia (FA) is a rare genetic disease characterized by congenital defects, bone marrow failure, chromosomal instability, and cancer susceptibility. One hallmark of cells from FA patients is hypersensitivity to interstrand cross-linking agents, such as the chemotherapeutics cisplatin and mitomycin C (MMC). We have recently characterized a FANCD2/FANCI-associated nuclease, KIAA1018/FAN1, the depletion of which sensitizes human cells to these agents. However, as the down-regulation of FAN1 in human cells was mediated by siRNA and thus only transient, we were unable to study the long-term effects of FAN1 loss on chromosomal stability. We now describe the generation of chicken DT40 B cells, in which the FAN1 locus was disrupted by gene targeting. FAN1-null cells are highly sensitive to cisplatin and MMC, but not to ionizing or UV radiation, methyl methanesulfonate, or camptothecin. The cells do not display elevated sister chromatid exchange frequencies, either sporadic or MMC-induced. Interestingly, MMC treatment causes chromosomal instability that is quantitatively, but not qualitatively, comparable to that seen in FA cells. This finding, coupled with evidence showing that DT40 cells deficient in both FAN1 and FANCC, or FAN1 and FANCJ, exhibited increased sensitivity to cisplatin compared with cells lacking only FAN1, suggests that, despite its association with FANCD2/FANCI, FAN1 in DT40 cells participates in the processing of damage induced by interstrand cross-linking-generating agents also independently of the classical FA pathway.
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PMID:KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents. 2111 14

Fanconi anemia (FA) results from mutations in the FANC genes and is characterized by bone marrow failure, birth defects, and a high incidence of cancer. FANCG is a part of the FA core complex that is responsible for monoubiquitination of FANCD2 and FANCI. The precise role of the FA pathway is not well understood, although it may be involved in homologous recombination (HR), nonhomologous end joining, and translesion synthesis (TLS). Fancd2(-/-) mice have a more severe phenotype than Fancg(-/-), and other FA core complex-deficient mice, although both Fancg and Fancd2 belong to the same FA pathway. We hypothesized that Fancd2 deficiency results in a more severe phenotype because Fancd2 also has a FA pathway-independent function in the maintenance of genomic integrity. To test this hypothesis, we determined the level of DNA damage and genomic instability in Fancd2(-/-), Fancg(-/-), and wild-type controls. Fancd2(-/-) mice displayed a higher magnitude of chromosomal breakage and micronucleus formation than the wild-type or Fancg(-/-) mice. Also, DNA strand breaks were increased in Fancd2(-/-) but not in Fancg(-/-) mice. In addition, Fancd2(-/-) mice displayed an elevated frequency of DNA deletions, resulting from HR at the endogenous p(un) locus. In contrast, in Fancg(-/-) mice, the frequency of DNA deletions was decreased. Thus, Fancd2 but not Fancg deficiency results in elevated chromosomal/DNA breakage and permanent genome rearrangements. This provides evidence that Fancd2 plays an additional role in the maintenance of genomic stability than Fancg, which might explain the higher predisposition to cancer seen in the Fancd2(-/-) mice.
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PMID:Genomic instability in mice is greater in Fanconi anemia caused by deficiency of Fancd2 than Fancg. 2111 69

In recent years there has been intense investigation and rapid progress in our understanding of the cellular responses to various types of endogenous and exogenous DNA damage that ensure genetic stability. These studies have identified numerous roles for ubiquitylation, the post-translational modification of proteins with single ubiquitin or poly-ubiquitin chains. Initially discovered for its role in targeting proteins for degradation in the proteasome, ubiquitylation functions in a variety of regulatory roles to co-ordinate the recruitment and activity of a large number of protein complexes required for recovery from DNA damage. This includes the identification of essential DNA damage response genes that encode proteins directly involved in the ubiquitylation process itself, proteins that are targets for ubiquitylation, proteins that contain ubiquitin binding domains, as well as proteins involved in the de-ubiquitylation process. This review will focus on the regulatory functions of ubiquitylation in three distinct DNA damage responses that involve ubiquitin modification of proliferating cell nuclear antigen (PCNA) in DNA damage tolerance, the core histone H2A and its variant H2AX in double strand break repair (DSBR) and the Fanconi anaemia (FA) proteins FANCD2 and FANCI in cross link repair.
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PMID:Regulatory functions of ubiquitin in diverse DNA damage responses. 2134 28

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, congenital abnormalities, and an increased risk for cancer and leukemia. Components of the FA-BRCA pathway are thought to function in the repair of DNA interstrand cross-links. Central to this pathway is the monoubiquitylation and chromatin localization of 2 FA proteins, FA complementation group D2 (FANCD2) and FANCI. In the present study, we show that RAD18 binds FANCD2 and is required for efficient monoubiquitylation and chromatin localization of both FANCD2 and FANCI. Human RAD18-knockout cells display increased sensitivity to mitomycin C and a delay in FANCD2 foci formation compared with their wild-type counterparts. In addition, RAD18-knockout cells display a unique lack of FANCD2 and FANCI localization to chromatin in exponentially growing cells. FANCD2 ubiquitylation is normal in cells containing a ubiquitylation-resistant form of proliferating cell nuclear antigen, and chromatin loading of FA core complex proteins appears normal in RAD18-knockout cells. Mutation of the RING domain of RAD18 ablates the interaction with and chromatin loading of FANCD2. These data suggest a key role for the E3 ligase activity of RAD18 in the recruitment of FANCD2 and FANCI to chromatin and the events leading to their ubiquitylation during S phase.
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PMID:The E3 ubiquitin ligase RAD18 regulates ubiquitylation and chromatin loading of FANCD2 and FANCI. 2135 96

Interstrand cross-links (ICLs) block replication and transcription and thus are highly cytotoxic. In higher eukaryotes, ICLs processing involves the Fanconi anemia (FA) pathway and homologous recombination. Stalled replication forks activate the eight-subunit FA core complex, which ubiquitylates FANCD2-FANCI. Once it is posttranslationally modified, this heterodimer recruits downstream members of the ICL repairosome, including the FAN1 nuclease. However, ICL processing has been shown to also involve MUS81-EME1 and XPF-ERCC1, nucleases known to interact with SLX4, a docking protein that also can bind another nuclease, SLX1. To investigate the role of SLX4 more closely, we disrupted the SLX4 gene in avian DT40 cells. SLX4 deficiency caused cell death associated with extensive chromosomal aberrations, including a significant fraction of isochromatid-type breaks, with sister chromatids broken at the same site. SLX4 thus appears to play an essential role in cell proliferation, probably by promoting the resolution of interchromatid homologous recombination intermediates. Because ubiquitylation plays a key role in the FA pathway, and because the N-terminal region of SLX4 contains a ubiquitin-binding zinc finger (UBZ) domain, we asked whether this domain is required for ICL processing. We found that SLX4(-/-) cells expressing UBZ-deficient SLX4 were selectively sensitive to ICL-inducing agents, and that the UBZ domain was required for interaction of SLX4 with ubiquitylated FANCD2 and for its recruitment to DNA-damage foci generated by ICL-inducing agents. Our findings thus suggest that ubiquitylated FANCD2 recruits SLX4 to DNA damage sites, where it mediates the resolution of recombination intermediates generated during the processing of ICLs.
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PMID:Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway. 2146 21


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