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)

The Fanconi anemia (FA) core complex plays a crucial role in a DNA damage response network with BRCA1 and BRCA2. How this complex interacts with damaged DNA is unknown, as only the FA core protein FANCM (the homolog of an archaeal helicase/nuclease known as HEF) exhibits DNA binding activity. Here, we describe the identification of FAAP24, a protein that targets FANCM to structures that mimic intermediates formed during the replication/repair of damaged DNA. FAAP24 shares homology with the XPF family of flap/fork endonucleases, associates with the C-terminal region of FANCM, and is a component of the FA core complex. FAAP24 is required for normal levels of FANCD2 monoubiquitylation following DNA damage. Depletion of FAAP24 by siRNA results in cellular hypersensitivity to DNA crosslinking agents and chromosomal instability. Our data indicate that the FANCM/FAAP24 complex may play a key role in recruitment of the FA core complex to damaged DNA.
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PMID:Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. 1731 22

Inherited breast cancer is associated with germline mutations in ten different genes in pathways critical to genomic integrity. BRCA1 and BRCA2 mutations confer very high risks of breast and ovarian cancer. p53 and PTEN mutations lead to very high breast cancer risks associated with rare cancer syndromes. Mutations in CHEK2, ATM, NBS1, RAD50, BRIP1, and PALB2 are associated with doubling of breast cancer risks. In addition, biallelic mutations in BRCA2, BRIP1, and PALB2 cause Fanconi anemia. The convergence of these genes in a shared role reveals underlying biology of these illnesses and suggests still other breast cancer genes.
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PMID:Ten genes for inherited breast cancer. 1729 21

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.
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PMID:Gene-specific selection against experimental fanconi anemia gene inactivation in human cancer. 1738 68

The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network involving breast cancer susceptibility gene products, BRCA1 and BRCA2. The complex consists of eight FA proteins, including a ubiquitin ligase (FANCL) and a DNA translocase (FANCM), and is essential for monoubiquitination of FANCD2 in response to DNA damage. Here, we report a novel component of this complex, termed FAAP100, which is essential for the stability of the core complex and directly interacts with FANCB and FANCL to form a stable subcomplex. Formation of this subcomplex protects each component from proteolytic degradation and also allows their coregulation by FANCA and FANCM during nuclear localization. Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability. Our study identifies FAAP100 as a new critical component of the FA-BRCA DNA damage response network.
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PMID:FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. 1739 47

We have recently described an involvement of H2AX into the Fanconi anemia (FA) BRCA pathway through recruitment of FA protein FANCD2 to the sites of stalled replication forks. We showed that BRCA1 mediates the recruitment of FANCD2 by gammaH2AX to damaged chromatin and cells deficient or depleted of H2AX exhibit an FA-like phenotype, including an excess of chromatid-type chromosomal aberrations and hypersensitivity to MMC. Here, we discuss a model for the FA pathway and how it could partially explain the common phenotypes of H2AX, BRCA2 and FA deficiencies.
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PMID:New roads to FA/BRCA pathway: H2AX. 1747 Oct 25

Autosomal dominant cancer predisposition genes for common cancers such as breast cancer and colorectal cancer have been well recognized for over a decade. Monoallelic mutations in these genes are associated with high risks of adult-onset cancer. In recent years, it has become apparent that biallelic mutations in some of these genes, such as BRCA2, MSH2 and MLH1, result in distinctive phenotypes, including childhood cancer predisposition. Conversely, it has also become evident that some genes which cause autosomal recessive cancer predisposition syndromes such as Fanconi anaemia and ataxia-telangiectasia are associated with modestly increased risks of adult cancers in monoallelic mutation carriers. These observations raise interesting implications with respect to the identification and phenotypic characterization of cancer predisposition genes.
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PMID:Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players. 1761 48

Fanconi anemia (FA) is a rare recessive hereditary disease characterized clinically by congenital defects, progressive bone-marrow failure, and cancer predisposition. Cells from FA patients exhibit hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC). To date, at least 12 FA genes have been found deleted or mutated in FA cells, and 10 FA gene products form a core complex involved in FA/BRCA2 DNA repair pathway?FA pathway. The ubiquitin E3 ligase FANCL, an important factor of FA core complex, co-functions with a new ubiquitin conjugating enzyme UBE2T to catalyze the monoubiquitination of FANCD2. FANCD2-Ub binds BRCA2 to form a new complex located in chromatin foci and then take part in DNA repair process. The deubiquitylating enzyme USP1 removes the mono-ubiquitin from FANCD2-Ub following completion of the repair process, then restores the blocked cell cycle to normal order by shutting off the FA pathway. In a word, the FANCD2 activity adjusted exquisitely by ubiquitination and/or deubiquitination in vivo may co-regulate the FA pathway involving in variant DNA repair pathway.
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PMID:Fanconi anemia and ubiquitination. 1764 42

Proteasome inhibitors sensitize tumor cells to DNA-damaging agents, including ionizing radiation (IR), and DNA cross-linking agents (melphalan and cisplatin) through unknown mechanisms. The Fanconi anemia pathway is a DNA damage-activated signaling pathway, which regulates cellular resistance to DNA cross-linking agents. Monoubiquitination and nuclear foci formation of FANCD2 are critical steps of the Fanconi anemia pathway. Here, we show that proteasome function is required for the activation of the Fanconi anemia pathway and for DNA damage signaling. Proteasome inhibitors (bortezomib and MG132) and depletion of 19S and 20S proteasome subunits (PSMD4, PSMD14, and PSMB3) inhibited monoubiquitination and/or nuclear foci formation of FANCD2, whereas depletion of DSS1/SHFM1, a subunit of the 19S proteasome that also directly binds to BRCA2, did not inhibit FANCD2 monoubiquitination or foci formation. On the other hand, DNA damage-signaling processes, such as IR-induced foci formation of phosphorylated ATM (phospho-ATM), 53BP1, NBS1, BRCA1, FANCD2, and RAD51, were delayed in the presence of proteasome inhibitors, whereas ATM autophosphorylation and nuclear foci formation of gammaH2AX, MDC1, and RPA were not inhibited. Furthermore, persistence of DNA damage and abrogation of the IR-induced G(1)-S checkpoint resulted from proteasome inhibition. In summary, we showed that the proteasome function is required for monoubiquitination of FANCD2, foci formation of 53BP1, phospho-ATM, NBS1, BRCA1, FANCD2, and RAD51. The dependence of specific DNA damage-signaling steps on the proteasome may explain the sensitization of tumor cells to DNA-damaging chemotherapeutic agents by proteasome inhibitors.
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PMID:Proteasome function is required for DNA damage response and fanconi anemia pathway activation. 1767 Dec 10

Fanconi anaemia (FA) has recently become an attractive model to study breast cancer susceptibility (BRCA) genes, as three FA genes, FANCD1, FANCN and FANCJ, are identical to the BRCA genes BRCA2, PALB2 and BRIP1. Increasing evidence shows that FA proteins function as signal transducers and DNA-processing molecules in a DNA-damage response network. This network consists of many proteins that maintain genome integrity, including ataxia telangiectasia and Rad3 related protein (ATR), Bloom syndrome protein (BLM), and BRCA1. Now that the gene that is defective in the thirteenth and last assigned FA complementation group (FANCI) has been identified, I discuss what is known about FA proteins and their interactive network, and what remains to be discovered.
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PMID:Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. 1776 2

Fanconi anemia (FA) patients have an increased risk for squamous cell carcinomas (SCCs) at sites of predilection for infection with high-risk human papillomavirus (HPV) types, including the oral cavity and the anogenital tract. We show here that activation of the FA pathway is a frequent event in cervical SCCs. We found that FA pathway activation is triggered mainly by the HPV type 16 (HPV-16) E7 oncoprotein and is associated with an enhanced formation of large FANCD2 foci and recruitment of FANCD2 as well as FANCD1/BRCA2 to chromatin. Episomal expression of HPV-16 oncoproteins was sufficient to activate the FA pathway. Importantly, the expression of HPV-16 E7 in FA-deficient cells led to accelerated chromosomal instability. Taken together, our findings establish the FA pathway as an early host cell response to high-risk HPV infection and may help to explain the greatly enhanced susceptibility of FA patients to squamous cell carcinogenesis at anatomic sites that are frequently infected by high-risk HPVs.
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PMID:The human papillomavirus type 16 E7 oncoprotein activates the Fanconi anemia (FA) pathway and causes accelerated chromosomal instability in FA cells. 1789 70


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