the preCancer cells, persistent replication in the presence of genotoxic stress also requires an intact DNA repair pathway. So tract cancer DNA repair aberrant addicted to one or more repair pathways kept intact to maintain their upright growth. This can be ended a mechanism of resistance to certain types of chemotherapy and radiation DNA beautiful. Improve narrow path upregulated DNA repair K DNA TW-37 can Sch, And the anti-tumor activity of t by radiation and chemotherapy. These signaling upregulated DNA Sch The and repair pathways that cancer cells to cancer are addicted may also represent, k s Achilles heel Nnte a specific inhibitor of the path to a selective anti-tumor effect in preventing lead repair of DNA Sch The through the use of inh pensions principle of synthetic lethality t. Synthetic lethality zun T Highest described by the geneticist Dobzhansky in the 1940s, refers to the synthetic lethality t an interaction in which the individual deletion of the two genes has no effect, but combined deletion of both genes is cytotoxic.
Synthetic lethality Tk can Also in the treatment of cancer, as in the case of Krebspr Disposition syndromes such as BRCA1 or BRCA2 are exploited. The latter genes play an r Key in the maintenance of genome integrity t Because of their involvement in human resources, a gr Ere repair pathway for DNA Bezirksschulr-run. Cancer cells with aberrant HR secondary Re BRCA gene mutations h nts Much BER SSBR for sustainability. The enzyme poly-1 is essential for polymerase DAPT SSBR BER. 1 inhibition of PARP leads to an accumulation of unrepaired SSB and synthetically is lethal in BRCA1 or BRCA2 mutations due to accumulation of replication fork collapse and t Dlichen CBD as detected by two independent-Dependent groups. Recent data suggest that activation of the NHEJ for synthetic lethality t Required, suggesting that repair errors replicationassociated CBD with the cytotoxicity t PARP inhibitors in cells HRdefective is connected.
W PARPi while effective in the case of BRCA1 or BRCA2, the paradigm of the synthetic lethality t of other cancers, including sporadic F Lle agrees on are. HR is a complex process, Including many factors Lich ATM, ATR, CHK1, RAD51 and its homologs, FANC proteins, MRE11 RAD50 NBS1 and loss of function in one of the components are m May receive the Anf Susceptibility give for PARPi. PARPi k can Also synthetic lethal hidden lacing occurs where epigenetic BRCA. This effect of sporadic breast and was called ovarian cancer BRCAness, but it is now clear that this view is centered misleading because BRCA defects in components of other human resources with a variety of cancers associated example, defects in ATM cell lymphoma mantle , k can also benefit from the therapy PARPi. EMSY and PTEN were also involved, because the activity of t to adjust other components of the HR. PARP-structure-function relationship at the moment a total of 16 fa PARP