Chromatin Remodeling Enzyme May Be Chemotherapy Target

Knocking down intracellular Parp1 levels with siRNA or inhibiting Parp1 activity with small molecules reduces repair of ssDNA breaks. In the absence of Parp1, when these breaks are encountered during DNA replication, the replication fork stalls and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via homologous recombination (HR) repair, an error-free repair mechanism. Thus, if the HR pathway is functioning, cells without functioning Parp1 do not show an unhealthy phenotype, and in fact, Parp1 knockout mice show no negative phenotype and no increased incidence of tumor formation.

Studies have shown that the protein products of the BRCA1 and BRCA2 genes are at least partially necessary for the HR pathway to function. Therefore, cells that are deficient in BRCA1 or BRCA2 have been shown to be highly sensitive to Parp1 inhibition or knockdown, resulting in cell death by apoptosis, in stark contrast to cells with at least one good copy of both BRCA1 and BRCA2. Since many breast cancers have defects in the BRCA1 / BRCA2 HR repair pathway, it has been suggested that Parp1 inhibitors may prove highly effective, due to the high sensitivity of the tumors to the inhibitor and the lack of deleterious effects on the remaining healthy cells with functioning BRCA HR pathways.

Investigators at the Stower's Institute for Medical Research (Kansas City, MO, USA) reported in the August 6, 2009, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) that Alc1 interacts with Parp1 to form a complex with strong chromatin remodeling activity.

"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,” said senior author Dr. Ron Conaway, professor of biochemistry and molecular biology at the Stower's Institute. "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.”

Since Parp1 inhibitors block Alc1 activities in vitro and in cancer cells growing in culture, it may be that drugs targeting Alc1 function could also be useful in the treatment of the disease.

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Stower's Institute for Medical Research