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Note for: PARP and PARG inhibitors in cancer treatment Doi: 10.1101/gad.334516.119 -         Chemotherapy and radiotherapy are nonselectively means of killing cancer cells. -         PARP is the successful drug targeting DNA damage response -         It was first approved for treating cancer with BRCA mutated ovarian and breast cancer – using synthetic lethality approach -         PAPR inhibitor destabilize replication fork o    Trap PARP to DNA o    Cell death through replication stress-induced mitotic catastrophe -         Inhibition of PARG – exacerbate replication deficiencies of cancer cells -         Highlight 4 PARP inhibitors used in cancer therapy o    Olaparib o    Rucaparib o    Niraparib o ...

Note: Topoisomerases as anticancer targets (doi: 10.1042/BCJ20160583) topoisomerase poisoning -- replication fork arrest and DSB formation. Side effect of topo-II -- development of secondary cancers and cardiotoxicity. There are two types of DNA topoisomerases, type I and type II. – Actually it should be 3? Type I topoisomerases break one DNA strand of duplex DNA to allow either the passage of the other DNA strand through the break or the rotation of downstream DNA duplex about the break, and then reseal the broken strand. Topo-I (each subtype has different mechanism); 1.TopoIA -- requires nick or single-stranded region to bind 2.TopoIB -- cleave one strand of duplex DNA 3.TopoIC -- cleave one strand of duplex DNA Type II topo isomerases alter the linking number in steps of two by breaking both DNA strands of duplex DNA. There are two subtypes of type II topoisomerases (working as homodimer), type IIA and type IIB. Each subtype of topoisomerase is ...

Note: Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy (doi: 10.1016/j.chembiol.2017.08.027) Process that maintain genome integrity in normal cells - it will help cancer to develop resistance to radiation and DNA-damaging chemotherapeutics. New target; RAD51 recombinase, RAD52, and MRE11 nuclease, WRN DNA helicase. Synthetic lethality - two individual mutations but when combined  resulting in lethal phenotype. Hartwell, is the first guy who initiated the synthetic lethality with the cancer baring the DNA-repair proteins defect. Also, cancer that addict to particular DNA repair mechanism. Therefore, the target for synthetic lethality is that finding the protein that the cancer cell relied on for viability (but less important in normal cell) and inhibit theirs function. Synthetic lethality; two types 1.between-pathway (each backup for each other) 2.In-pw synthetic lethality, mutation either way of revers...

Note for: Characterization of environmental chemicals with potential for DNA damage using isogenic DNA repair-deficient chicken DT40 cell lines (doi: 10.1002/em.20656) US Tox21 program -- evaluate the detection of genotoxic cpds. This study focused on cytotoxicity by using DT40 with deficient in DNA repair pathway. Using 7-isogenic DNA repair-deficient pw cell line to identify the types of DNA damage. Criteria to judge; 1.clastogenicity (ability to break the DNA) in mutant and WT 2.ability to induce gH2Ax positive foci by melphalan 3.72-hr viability through the liquid assay 4.using more DNA repair deficient cell lines to clearly identify the damage induced 5.involvement of ROS in induction of DNA damage At the end, it proposed that DT40 and theirs DNA-repaired deficient lines are useful tool to detect 1.genotoxic cmp. 2.identify the nature of DNA damage of the challenges 3.analyzing mechanism of mutagenesis Rational; Because of the number of chemica...