The packaging and unpackaging of genomic DNA and its associated proteins is called chromatin remodeling. It regulates a host of fundamental cellular processes including,
- Gene transcription
- DNA repair
- Programmed cell death
- Cell Fate
Scientists at the Stowers Institute for Medical Research have come up with their latest study that untangles the particular details of how these architectural modifications are controlled. The respective study is based upon a series of biochemical experiments revealing that chromatin remodeling enzyme and suspected oncogene Amplified in Liver Cancer 1 (ALC1) is activated through an unusual mechanism. In the presence of its activators, it undergoes a shift in its shape.
The findings of the research team identify a new instrument in the molecular repertoire of cells with chromatin-remodeling tools and a potential cancer therapeutic target. This respective research study is issued in the Journal of Biological Chemistry.
Chromatin remodeling enzymes make DNA accessible for repair and gene transcription. Previously, it was figured out that ALC1 required protein partners to activate its remodeling function. ALC1 and its genre have a common protein domain called SNF2. It utilizes the energy of ATP hydrolysis to move nucleosomes around; a process called nucleosome sliding.
Scientists were surprised to know that ALC1 has a distinctive macrodomain not found on any other SNF2 family member. In addition, while most ATP-dependent chromatin remodelers function as large multi-protein complexes, ALC1 appeared to work by itself. Similarly, where most of its family members readily exhibited nucleosome sliding activity in vitro, ALC1 was not only a lone ranger but also completely dead on its own.
ALC1 requires sidekicks for activation
Scientists deduced that despite the independent functioning of ALC1, the respective gene needs a boost from a couple of sidekicks.
PARP1 is an enzyme that responds to several kinds of DNA damage. Furthermore, NAD+ is the substrate by which PARP1 transfers chains of poly (ADP-ribose) onto itself and other target proteins. Only when PARP1 and NAD+ are on the scene does ALC1 spring into action. It alters the accessibility of DNA by shifting nucleosomes around. This activation of ALC1 occurs via a series of physical interactions. The unique macrodomain of ALC1 can bind PAR resulting in protein-protein interactions between ALC1 and PARP1. The trio of PARP1, NAD+, and ALC1 presented a stable complex. The two allosteric effectors were seen to alter ALC1’s state from dormant to active.
Currently, there is very little known about ALC1 except for its role in remodeling. However, it is found in excess in hepatocellular carcinoma cells and also overexpression of ALC1 in mice induces spontaneous tumors. Thus, it is regarded as a possible oncogene.
On the other hand, PARP1 is known as a potential anticancer drug target. It is important in maintaining genomic integrity e.g. in breast cancer cells lacking BRCA1 or BRCA2 function, blocking PARP could effectively remove the cells’ last line of defense against DNA-damaging chemotherapy agents.
The research scientists are looking forward to extending a better understanding of the in-depth biochemistry of ALC1 and PARP1. This will surely lead to new or more refined therapeutic strategies.