Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant pleural mesothelioma is an asbestos-related multi-resistant tumour with increasing incidence worldwide. Well-characterized snap-frozen normal parietal, visceral pleura and mesothelioma samples were analysed with Affymetrix Human Genome U133 Plus 2.0 GeneChip oligoarray of 38500 genes. We discovered a close relation between gene profile and resistance towards topoisomerase poisons, alkylating agents, antitubulines, antifolates, platinum compounds and radiation therapy. Target genes of chemo- (e.g. TOP2A, BIRC5/Survivin and proteasome) and radiotherapy (e.g. BRCA2, FANCA, FANCD2, CCNB1 and RAD50) were significantly overexpressed. The Fanconi anemia/BRCA2 pathway, responsible for homologous recombination DNA repair appears as a key pathway in both chemo- and radio-resistance of mesothelioma. Leukocyte trans-endothelial migration gene down-regulation could partly explain resistance against immunological therapies. Gene expression features found in other resistant cancer types related to DNA repair and replication are shared by mesothelioma and could represent general features of tumour resistance. Targeted suppression of some of those key genes and pathways combined with chemotherapy or radiation could improve the outcome of mesothelioma therapy. We propose CHEK1, RAD21, FANCD2 and RAN as new co-targets for mesothelioma treatment. The pro-angiogenic AGGF1 mRNA and protein was highly overexpressed in all tumours and may serve as a target for anti-angiogenic treatment. Overexpression of NQO1 may render mesothelioma sensitive to the novel compound beta-Lapachone.
 ...
PMID:Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets. 1938 Jan 73

FANCM is a component of the Fanconi anemia (FA) core complex and one FA patient (EUFA867) with biallelic mutations in FANCM has been described. Strikingly, we found that EUFA867 also carries biallelic mutations in FANCA. After correcting the FANCA defect in EUFA867 lymphoblasts, a "clean" FA-M cell line was generated. These cells were hypersensitive to mitomycin C, but unlike cells defective in other core complex members, FANCM(-/-) cells were proficient in monoubiquitinating FANCD2 and were sensitive to the topoisomerase inhibitor camptothecin, a feature shared only with the FA subtype D1 and N. In addition, FANCM(-/-) cells were sensitive to UV light. FANCM and a C-terminal deletion mutant rescued the cross-linker sensitivity of FANCM(-/-) cells, whereas a FANCM ATPase mutant did not. Because both mutants restored the formation of FANCD2 foci, we conclude that FANCM functions in an FA core complex-dependent and -independent manner.
 ...
PMID:Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M. 1942 27

Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) and BRCA proteins occurs in several cancer types, including lung and breast cancer, rendering the affected tumors potentially hypersensitive to DNA crosslinking agents. However, the cytotoxicity of other commonly used cancer therapeutics in cells with FA/BRCA pathway defects remains to be defined. Building on earlier data that implicated BRCA1 and BRCA2 in the repair of DNA damage caused by the topoisomerase II poison etoposide, we studied the role of FANCD2 in mediating resistance to several topoisomerase II poisons. We establish that the loss of FANCD2 increases cell death in response to etoposide. FANCD2 promotes homologous recombination repair (HRR) and prevents DNA double-strand break formation and chromosomal aberrations in etoposide-treated cells. Strikingly, this function of FANCD2 is independent of FANCD2 foci formation and of FANCA, which is a member of the FA core complex upstream of FANCD2 mono-ubiquitination. Thus, FANCD2 appears to promote HRR in a mono-ubiquitination-independent manner in conjunction with BRCA1/2. These data add to an emerging body of evidence indicating that the FA pathway is not linear and that several protein subcomplexes with different functions exist. Our findings are potentially relevant for predicting the sensitivity of lung and breast cancers to etoposide and doxorubicin, respectively.
 ...
PMID:FANCD2 but not FANCA promotes cellular resistance to type II topoisomerase poisons. 2141 16