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Researchers Identify Protein Linked To Cancer- Drug Resistance

Researchers from University of Cambridge identified a protein complex probably responsible for resistance to new anti-cancer drugs

The cells have various repair mechanisms to fix DNA damage. The simplest mechanism for repairing DNA breaks is known as ‘non-homologous end-joining’ (NHEJ) that operates by gluing together the broken DNA strands. However, the mechanism is imperfect and can result in deletions of segments of DNA. Homologous recombination (HR) is a more accurate mechanism that operates with a copy of the DNA as a reference text to fill in any missing gaps. However, both the processes work in competition against each other and it is observed that when the balance is tipped in favor of HR, it leads to the cells opting HR for repairing the DNA damage. BRCA1 is one of the proteins involved in HR. However, some people carry a harmful BRCA1 mutation that leads to more susceptibility to cancer. Although, normal cells in these people comprise a harmful BRCA1 gene, one beneficial copy of the gene is present that can still carry out HR mechanism. However, cancer cells in such cases do not contain the beneficial copy of BRCA1 that leads to loss in capability of the cells to carry out homologous recombination.

PARP-inhibitor drugs enable a double-strand DNA break. This breakdown can only be repaired by homologous recombination, hence it leads to death of BRCA1-negative cancer cells. However, some patients taking PARP inhibitors develop resistance to the drugs. The researchers used cutting-edge CRISPR-Cas 9 gene editing techniques to screen cancer cells with the BRCA1 mutation and identify which genes drive resistance. It was observed that two genes that produce a protein complex— Shieldin—plays an important role in Non-homologous end joining (NHEJ)  binding at the site of the broken strands of DNA. Shieldin is the major factor responsible for response of patients to PARP inhibitors. The researchers transplanted BRCA1 mutation in mice models to confirm their findings. It was observed that mice with low levels of Shieldin from the outset did not respond to the PARP inhibitors. Furthermore, mice that evolved resistance to the drugs had tumors with low levels of Shieldin. The research was published in Nature Cell Biology on July 18, 2018.