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Biomap#92

Title: DNA repair, cancer and anticancer agents
 
Legend: Genome integrity is continuously threatened by both endogenous (e.g. reactive oxygen species produced by normal metabolism, DNA replication "errors") and exogenous (ultraviolet light, ionizing radiations, chemical carcinogens) factors and is maintained by a complex network of more than 130 DNA repair-related proteins. Eukaryotic cells are characterized by multiple interconnected and in part redundant DNA damage checkpoints as well as DNA repair pathways that can "sense" DNA damage and respond to it with a cascade of molecular reactions leading to the restitutio ad integrum of the DNA molecule in most circumstances. Six main DNA repair pathways can be identified: 1) direct reversal repair; 2) nucleotide excision repair (NER); 3) base excision repair (BER); 4) homologous recombination (HR); 5) non-homologous end joining (NHEJ); and 6) mismatch repair (MMR). In case these pathways fail to repair the DNA damage, the same molecular machinery can sense the DNA defect as a "danger" and can trigger programmed cell death. This fail-safe system guarantees that: 1) potentially dangerous DNA damage is transmitted to the cell progeny with consequent propagation of the defect to a growing number of cells; 2) potentially oncogenic genetic alterations give rise to cell transformation. However, when the DNA damage neither is repaired nor induces apoptotic elimination of the "diseased" cell, DNA defects accumulate and are propagated through the cell progeny: under these circumstances, oncogenesis may occur, classically through the activation of oncogenes and inactivation of tumor suppressor genes. The evidence of genetic/genomic integrity/stability in most tumor types and the identification of cancer predisposition syndromes linked to defects in DNA repair related proteins lend support to the theory that these proteins play a key role in opposing cancer development and progression. In particular, the somatic/germ-line impairment of DNA repair related genes would be responsible of the so called "mutator phenotype" exhibited by cancers (whereby the mutation rate is higher than in normal cells). REFERENCES: [1] Ishikawa T, Cancer Sci 2004, 95:112-7. [2] Li C, Int J Cancer 2009, 124:999-1007. [3] Martin SA, Curr Opin Genet Dev 2008, 18:80-6. [4] Helleday T, Nat Rev Cancer 2008, 8:193-204 CITED BIOMOLECULES: ALKBH2 (alkylation repair homolog 2), ALKBH3, APE1 (APEX nuclease 1), ATM (ataxia teleangectasia mutated), ATR (ataxia telengectasia and Rad3 related), Atrip (ATR interacting protein), BAX (BCL2-associated X protein), BLM (Bloom syndrome, RecQ helicase-like), BRCA1 (breast cancer 1, BRCC1), BRCA2 (FANCD1, BRCC2), Cdc25 (cell division cycle 25 C), CDK (cyclin dependent kinase), CHK1 (checkpoint kinase 1), CHK2, CSA (Cockayne syndrome 1, ERCC8), CSB (ERCC6), CUL4 (cullin 4), Cyclin, DDB2 (damage-specific DNA binding protein 2), DNA pol beta, (DNA polymerase beta), DNA pol delta, DNA pol epsilon, DNA pol eta, DNA pol III, DNA-PK (DNA-activated protein kinase), ERCC1 (excision repair cross-complementing rodent repair deficiency, complementation group 1), FANCA (Fanconi anemia, complementation group A), FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG (XRCC9), FANCI, FANCL, FANCM, H2AX (H2A histone family, member X), Ku70 (thyroid autoantigen 70kD, XRCC6), Ku80, Ligase I, Ligase III, Ligase IV, MCM2 (minichromosome maintenance complex component 2), MGMT (O6-methylguanine DNA methyltransferase), MLH1 (mutL protein homolog 1), MLH3, MPG (N-methylpurine-DNA glycosylase), MRE11 (MRE11 meiotic recombination 11 homolog), MSH2 (MutS protein homolog 2), MSH3, MSH6, MYH (MutY homolog), NBS1 (NLR family, pyrin domain containing 2, NLRP2), OGG1 (8-oxoguanine DNA glycosylase), OxoG (oxoguanine), p21 (CDKN1A), p53, PAR (poly ADP ribose), PARG (PAR glycohydrolase), PARP (PAR polymerase), PLK1 (polo-like kinase 1), PMS1 (PMS1 postmeiotic segregation increased 1), PMS2, Puma (p53 upregulated modulator of apoptosis, BBC3), RAD17 (RAD17 homolog), RAD50, RAD51 (BRCC5), RAD51B, RAD51C, RAD51D, RNA pol II (RNA polymerase II), ROS (reactive oxygen species), RPA (replication protein A1), SMUG1 (single-strand-selective monofunctional uracil-DNA glycosylase 1), TDG (thymine-DNA glycosylase), TTDA (trichothiodystrophy, GTF2H5), UNG (uracil-DNA glycosylase), WEE1 (WEE1 homolog), X-box (RBX1), XPA (xeroderma pigmentosum, complementation group A), XPB (ERCC3), XPC, XPD (ERCC2), XPE (DDB1), XPF (ERCC4, RAD1), XPG (ERCC5), XRCC1 (X-ray repair complementing defective repair in Chinese hamster cells 1), XRCC2, XRCC3, XRCC4. CITED DRUGS: ABT-888, Actinomycin-D, AGO14699, AZD-2281, BCNU, Bleomycin, BSI-201, Busulfan, Carboplatin, CCNU, Chlorambucil, Cisplatin, Cyclophosphamide, Dacarbazine, Ifosfamide, INO-1001, Lomeguatrib, MeCCNU , Melphalan, Mitomycin-C, O6-benzylguanine, Oxaliplatin, Procarbazine, Streptozotocin, Temozolomide, Thiotepa, XL844
Author: The MMMP Team (updated: April 2009)

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