Researchers at University of Copenhagen and colleagues used a network-based proteomics approach to identify shieldin, a protein complex that sensitizes BRCA1-deficient cancers to PARP inhibitors, suggesting that shieldin component levels could guide precision medicine strategies.
In a paper published in Cell, the team used a biotin labeling- and mass spectrometry-based method to generate spatially resolved network maps of DNA repair proteins involved in DNA damage response pathways.
The network analysis identified a protein complex involved in the tumor protein p53 binding protein 1 (TP53BP1; 53BP1) pathway called shieldin, which promotes non-homologous end joining (NHEJ)-mediated DNA repair, telomere maintenance and immunoglobulin class-switch recombination.
The shieldin complex comprises the adaptor protein mitotic arrest deficient 2 like 2 (MAD2L2; REV7) and three newly identified proteins, dubbed REV7-interacting novel NHEJ regulator 1 (RINN1), family with sequence similarity 35 member A (FAM35A; RINN2) and chromosome 20 open reading frame 196 (C20ord196; RINN3).
The authors showed shieldin promoted NHEJ by suppressing DNA end resection. Excessive DNA end resection makes DNA ends unsuitable for NHEJ and instead promotes homology-directed repair, the DNA repair process mediated by tumor suppressor breast cancer 1 early onset (BRCA1). Cancers that lack BRCA1 are sensitive to PARP inhibitors, such as Lynparza olaparib from AstraZeneca plc (LSE:AZN; NYSE:AZN) and partner Merck & Co. Inc. (NYSE:MRK), since they cannot use homology-directed repair to repair double-stranded breaks that accumulate due to PARP deficiency.
However, the researchers found that deletion of shieldin components confers resistance to PARP inhibitors in BRCA1-deficient cells.
In BRCA1-deficient mouse embryonic fibroblasts and human osteocarcinoma cells, knockout of shieldin complex components increased resistance to Lynparza compared with normal expression, at least in part by restoring homology-directed repair. The authors suggest shieldin functions downstream of TP53BP1, whose depletion has also been shown to render BRCA1-deficient cells resistant to PARP inhibition.