Article Abstract

Synthetic lethality vs. synthetic viability due to PARP1 and BRCA2 loss

Authors: Xia Ding, Shyam K. Sharan

Abstract

The commentary entitled “Turning the concept of synthetic lethality in its head” by Parkes and Kennedy not only clearly highlighted our recent work on the genetic interaction between BRCA2 and PARP1 but also raised some valid questions (1,2). We would like to clarify that while our findings suggest that loss of PARP1 and BRCA2 can result in synthetic viability, it does not challenge the dogma of synthetic lethality by PARP inhibition in BRCA2-deficient cells. We found that although Brca2ko/ko mouse embryonic stem (ES) cells fail to survive, we could rescue their lethality by treating Brca2 heterozygous (Brca2ko/ko) cells with olaparib prior to Cre-mediated deletion of the conditional allele. Interestingly, these “rescued” Brca2ko/ko cells were found to be sensitive to olaparib, consistent with the concept of synthetic lethality. We obtained similar results in mouse hematopoietic stem cells (HSC), when mice carrying Brca2 conditional alleles were treated with olaparib and then the conditional alleles were deleted in the HSC. Like in the case of ES cells, we obtained viable Brca2ko/ko HSC, but they were still sensitive to olaparib. Our observations led us to conclude that the order of loss of PARP1 and BRCA2 is important. The two opposite outcomes i.e., synthetic viability and synthetic lethality are dependent on the order in which BRCA2 and PARP1 are lost. In BRCA2-deficient cells, PARP inhibition results in synthetic lethality. In contrast, in Parp1 deficient or PARP inhibited cells, when Brca2 is deleted, it results in cell viability. When PARP is inhibited or its levels are reduced, the cells are able to protect the replication fork from MRE11-mediated degradation, which contributes to cell viability when BRCA2 is deleted. Whether PARP inhibitor pretreatment can result in synthetic viability of other BRCA2 deficient cells, especially mammary epithelial cells remain to be explored. However, we did observe a significant increase in epithelial tumors in Parp1 heterozygous mice when Brca2 was deleted using Cre under the control of K14 promoter.