MRC Human Genetics Unit
Medical Research Council Human Genetics Unit

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Genomic Ribonucleotides Produce PARP-Trapping Lesions

RNASEH2 deficiency impairs ribonucleotide excision repair to confer PARP inhibitor sensitivity: July 2018

Targeted therapy for cancer uses drugs that attack specific types of cancer cell by preventing them from growing but have less impact on healthy cells. One example of such cancer drugs are PARP inhibitors, FDA-approved drugs used for treatment of breast and ovarian cancers with faulty BRCA1 or BRCA2 genes. PARP inhibitors block PARP1 protein and keep it tightly bound to sites of DNA breaks. This interferes with DNA replication, a process required for cells to divide, and is highly toxic to cancer cells when the BRCA1 or BRCA2 gene is faulty.

IGMM researchers with worldwide collaborators  sought to better understand how cells respond to PARP inhibition and determine if genetic faults in certain cancers could make them more sensitive.  Using cutting-edge CRISPR/Cas9-based gene-editing technology, they inactivated many different genes in human cells. They assessed changes in cell viability following treatment with olaparib (Lynparza), a clinically approved PARP inhibitor and identified a set of genes that, once inactivated, make cells more sensitive to PARP inhibition. These included an enzyme named RNase H2. Cells without RNase H2 have more damaged DNA than normal cells because their DNA contains ribonucleotides. The action of another enzyme, called topoisomerase 1, on ribonucleotides leads to DNA breaks and increases the frequency of PARP protein attaching to DNA. As a result, treatment with PARP inhibitors causes formation of numerous PARP protein-DNA complexes, which block cell division and lead to cell death. The researchers found that metastatic prostate cancer and chronic lymphocytic leukaemia cells often contain deletions in the RNASEH2B gene, leading to inactivation of the RNase H2 enzyme, suggesting that PARP inhibitors may be useful in other cancer types.

Links

Andrew Jackson research group

Dan Durocher research group: http://durocherlab.org/ 

Original article: Nature 559, 285–289 (2018)  https://doi.org/10.1038/s41586-018-0291-z

 

 

Schematic of PARP inhibitor effects on biological pathways and replication fork