NCB: protein discovery reveals why patients are resistant to new anticancer drugs

July 26, 2018 / Biovalley / a new study by researchers from Cambridge University has found a new protein complex that may explain why some patients are resistant to new revolutionary anticancer drugs, such as PARP inhibitors Source: cc0 public domain BRCA1 deficiency can cause breast, ovarian, prostate and other cancers, and also make these tumors highly sensitive to PARP inhibitors In order to study the mechanism of tumor drug resistance, researchers from Cambridge University conducted genome-wide crispr-cas9 synthetic survivability / drug resistance screening in BRCA1 deficient breast cancer cell lines treated with PARP inhibitors The researchers found two previously undetected proteins, c20orf196 and fam35a, which inactivate cells to produce strong resistance to PARP inhibitors Through mechanism study, the researchers found that c20orf196 and fam35a can form a complex, shield in (shld1 / 2), in which the carbon terminal oligonucleotide binding domain of fam35a binds to single strand DNA The researchers found that sheeldin, as a downstream effector of 53BP1 / Rif1 / mad2l2, can promote the end connection of DNA double strand breaks by limiting the excision of DNA double strand breaks (DSB), and counteract homologous recombination by antagonizing BRCA2 / Rad51 load in BRCA1 deficient cells It is worth noting that the inactivation of shieldin can increase the sensitivity of BRCA1 deficient cells to cisplatin, which indicates that patients can be treated according to the shld1 / 2 status of BRCA1 deficient tumors Based on these findings, researchers believe that human breast cancer cells with reduced shld1 / 2 expression have inherent or acquired resistance to PARP inhibitors Reference: harveer dev et al, shield complex promotes DNA end joining and counters homologous recommendation in BRCA1 null cells, Nature Cell Biology (2018) Doi: 10.1038/s41556-018-0140-1