Summerlin, M. | Search bioRxiv

bioRxiv2026

PNPLA3I148M is a novel regulator of bone mass independent of MASLD

Metabolic-dysfunction associated steatotic liver disease (MASLD) is the most common chronic liver disease. Fracture risk is increased among people with MASLD, however, the genetic contribution to risk is undetermined. PNPLA3I148M is a common SNP which accounts for most MASLD heritability and increases MASLD morbidity and mortality. However, PNPLA3I148M impact on bone is unexplored. To bridge this gap, we used a validated murine model of MASLD (DIAMOND mice) which received human PNPLA3 transgenes via adeno-associated vector serotype 8 (AAV8) and assessed bone morphology, cellularity, and transcriptomics. PNPLA3I148M was expressed in bone and associated with bone loss, decreased bone formation, increased bone resorption, and increased bone marrow adiposity. PNPLA3I148M reprogrammed the transcriptome in bone, enriching expression of pathways associated with fatty acid metabolism and hampering bone turnover. Notably, these findings occurred in the absence of MASLD. These findings suggest PNPLA3I148M possesses an intrinsic deleterious skeletal role.

physiology↗

bioRxiv2020

Discovery and Development of Novel DNA-PK Inhibitors by Targeting the unique Ku-DNA Interaction

DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) repair pathway and the DNA damage response (DDR). DNA-PK has therefore been pursued for the development of anti-cancer therapeutics in combination with ionizing radiation (IR). We report the discovery of a new class of DNA-PK inhibitors that act via a novel mechanism of action, inhibition of the Ku-DNA interaction. We have developed a series of highly potent and specific Ku-DNA binding inhibitors (Ku-DBis) that block the Ku-DNA interaction and inhibit DNA-PK kinase activity. Ku-DBis directly interact with the Ku and inhibit in vitro NHEJ, cellular NHEJ, and potentiate the activity of IR and radiomimetics. Analysis of Ku-null cells demonstrates that Ku-DBis cellular activity is a direct result of Ku inhibition, as Ku-null cells are insensitive to Ku-DBis. The utility of Ku-DBis was also demonstrated in a CRISPR gene-editing model where we demonstrate that the efficiency of gene insertion events was increased in cells pre-treated with Ku-DBis, consistent with inhibition of NHEJ and activation of homologous recombination to facilitate gene insertion. These data demonstrate the discovery and application of new series of compounds that modulate DNA repair pathways via a unique mechanism of action.

biochemistry↗