Stowers Institute's Conaway Lab researchers have unveiled a previously unknown function of a gene product called Amplified in Liver Cancer 1 (Alc1), it can play a major role in the onset of cancer.
The study conducted research in the Conaway Lab was led by Aaron Gottschalk, and co-authored by a University of Kansas Medical Center graduate student.
"We've been able to demonstrate that the protein encoded by the Alc1 gene is, in fact, a chromatin remodeling enzyme. By itself, this enzyme is inactive, but in the presence of a compound called NAD and another enzyme called poly (ADP-ribose) polymerase 1 (Parp1), its ability to move nucleosomes on DNA is strongly activated," they said.
Parp1 uses NAD to build a polymeric molecule, poly(ADP-ribose), that is coupled to Parp1 itself or to other proteins.
The researchers established that binding of a specific Alc1 region to poly(ADP-ribose) coupled to Parp1 helps recruit Alc1 to bind to and remodel nucleosomes.
"This finding is particularly interesting because Parp1 and poly(ADP-ribose) are known to play important roles in transcriptional regulation, DNA repair, and DNA replication, but how they do so is really not at all clear. Finding that Parp1 and poly(ADP-ribose) recruit the chromatin remodeling enzyme Alc1 to chromatin and activate Alc1 activity suggests a mechanism by which they might function," said Dr. Ron Conaway, Investigator and co-senior author on the publication.
Medical researchers at universities and pharmaceutical companies are investigating Parp inhibitors for treatment of cancer and other diseases.
The researchers have shown that Parp inhibitors block Alc1 activities in the test tube and cells, suggesting that the therapeutic activities of these inhibitors could be due in part to indirect affects on Alc1.
If true, drugs that target Alc1 function could also be useful in the treatment of disease.
The work has been published by the Proceedings of the National Academy of Science Early Edition.