Activating ALC1—with a little help from friends

Chromatin remodeling—the packaging and unpackaging of genomic DNA and its associated proteins—regulates a host of fundamental cellular processes including gene transcription, DNA repair, programmed cell death, as well as cell fate. Through a series of biochemical experiments, Stowers Investigators Ron Conaway, PhD, and Joan Conaway, PhD, and their team continue to unravel the finicky details of how these architectural alterations are controlled.

In their latest study, the researchers discovered that chromatin remodeling enzyme and suspected oncogene ALC1 (short for Amplified in Liver Cancer 1) is activated through an unusual mechanism: In the presence of its activators, PARP1 and NAD+, ALC1 undergoes a structural change, which switches on the enzyme’s chromatin-remodeling activity.

Apart from its role in modifying chromatin structure, not much is currently known about ALC1. It’s regarded as a possible oncogene, being found in excess in hepatocellular carcinoma cells, and because overexpression of ALC1 in mice induces spontaneous tumors. PARP1, on the other hand, has attracted plenty of interest as a potential anticancer drug target, due to its importance in maintaining genomic integrity.

“A better understanding of the in-depth biochemistry we’re uncovering on ALC1 and PARP1 may, in the long term, lead to new or more refined therapeutic strategies,” says Aaron Gottschalk, PhD, postdoctoral researcher and the study’s first author.

The study was published in the December 21, 2012, issue of the Journal of Biological Chemistry.