Can’t Stop the Signal

Drugs that inhibit the activity of an enzyme known as poly(ADP-ribose) polymerase 1, or PARP1, are currently under investigation for a number of cancers. PARP1 is known to play a fundamental role in regulating DNA damage repair, and its activity in cancer allows the disease to resist chemotherapy. However, it’s currently difficult to predict which patients will have treatment-resistant disease, because we don’t fully understand how PARP1 activation leads to DNA repair. New research from the University of Texas Southwestern Medical Center has yielded new technology that can provide additional insight into PARP1 signaling.

The researchers use highly sensitive mass spectrometry and chemical tagging to map the downstream signaling network of PARP1. “Specifically, it allows us to identify the proteins that are modified by PARP1 when the enzyme is activated,” explains senior author Yonghao Yu. “We have used our technique to look for proteins that are differentially modified in benign breast epithelial cells and in cells that signify different breast cancer subtypes. In our study (1), we found that PARP1 modifies different sets of proteins in these cells, generating highly heterogeneous signaling outputs or signatures. Most intriguing of all is the correlation we found between this PARP1 activation signature in different breast cancer cells and their potential response to chemotherapeutic agents.”

Although the current study was performed in breast cells, PARP1 inhibitors are being studied in many other cancer types, and the technology could potentially be applied to many human malignancies. “Our approach is still in its early stages,” cautions Yu, “but we are hoping our future research will lead to a PARP1 modification signature that can predict which patients might benefit from PARP1 inhibitor treatment.”