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నైరూప్య

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Jiri Kohoutek ,Hana Paculová, Juraj Kramara , Šárka Šimečková, Karel Souček, Ondřej Hylše, Kamil Paruch, Marek Svoboda and Martin Mistrik.

A broad spectrum of tumors develops resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly (ADP-ribose) polymerase 1/2 proteins and DNA damage response genes including BRCA1, a factor involved in homologous recombination–mediated DNA repair and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. Inhibitors of CHK1 have been shown to enhance the anti-cancer effect of DNAdamaging compounds. Since, loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival.