Epigenetics: Kinases Can Play Too
While most research surrounding epigenetic regulation has been on methyltransferases, acetyltransferases, and the corresponding reader/eraser enzymes, a new study shows that kinases can also play an important role in epigenetic regulation. In a study published in the February issue of Molecular Cell, a team of researchers led by Alexei V. Tulin at the Fox Chase Cancer Center, identify a new kinase-mediated mechanism of poly ADP-ribose polymerase-1 (PARP-1) activation and propose a novel class of inhibitors designed to block the newly identified mechanism.
Research has shown that PARP-1 plays a crucial role in cancer cell DNA repair, specifically in BRCA-related cancers, and it has been suggested that combining standard cancer therapies with PARP-1 inhibitors could be more effective. However, clinical trials of PARP-1 inhibitors have produced disappointing outcomes. Lead author Alexei V. Tulin says he believes many of the previous setbacks can be attributed to a general misconception of the mechanism of PARP-1 regulation.
While it has been known for some time that interaction with DNA or nucleosomes triggers PARP-1 activation, the details of the activation process have been unclear. Tulin and colleagues have identified a specific molecular mechanism responsible for regulating PARP-1.
The researchers report that a nuclear tandem kinase, JIL-1 phosphorylates the C terminus of the histone H2Av, changing and exposing previously hidden parts of the nucleosome; most importantly, histone H4 which stimulates PARP-1 enzymatic activity in the newly exposed surrounding chromatin, leading to further modification of histones and chromatin loosening.
Building on their findings, the researchers have begun to develop the next generation of PARP-1 inhibitors, designed to block the newly identified mechanism of PARP-1 activation. Tulin says the more specific inhibitors hold great promise for cancer treatment, “We expect that our targeted PARP1 inhibitors will be more effective at killing cancer cells while protecting important molecular pathways in normal cells.”
