Biology subjects

Sears, C. R.

Publications and source records attributed to Sears, C. R..

3 recordsLinked to original sources

bioRxiv2025

Cigarette Smoke and Decreased DNA Repair by Xeroderma Pigmentosum Group C Use a Double Hit Mechanism for Epithelial Cell Lung Carcinogenesis

Emerging evidence suggests a complex interplay of environmental and genetic factors in non-small cell lung cancer (NSCLC) development. Among these factors, compromised DNA repair plays a critical but incompletely understood role in lung tumorigenesis and concurrent lung diseases, such as chronic obstructive lung disease (COPD). In this study, we investigated the interplay between cigarette smoke, DNA damage and repair, focusing on the Nucleotide Excision Repair (NER) protein Xeroderma Pigmentosum Group C (XPC). We found decreased XPC mRNA expression in most NSCLCs compared to subject-matched, non-cancerous lung. In non-cancerous bronchial epithelial cells, cigarette smoke decreased NER, increased total DNA damage and resultant apoptosis, each exacerbated by XPC deficiency. In contrast, lung cancer cells exhibit greater resilience to cigarette smoke, requiring higher doses to induce comparable DNA damage and apoptosis, and are less reliant on XPC expression for survival. Importantly, XPC protects against chromosomal instability in benign bronchial epithelial cells, but not in lung cancer cells. Our findings support a "double hit" mechanism wherein early decreased XPC expression and resultant aberrant DNA repair, when combined with cigarette smoke exposure, may lead to loss of non-malignant epithelial cells (as observed in COPD), and contributes to early NSCLC transition through altered DNA damage response.

cancer biology↗

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↗

bioRxiv2017

Genetic architectures of larval pigmentation and color pattern in the redheaded pine sawfly (Neodiprion lecontei)

Pigmentation has emerged as a premier model for understanding the genetic basis of phenotypic evolution, and a growing catalog of color loci is starting to reveal biases in the mutations, genes, and genetic architectures underlying color variation in the wild. However, existing studies have sampled a limited subset of taxa, color traits, and developmental stages. To expand our sample of color loci, we performed quantitative trait locus (QTL) mapping analyses on two types of larval pigmentation traits that vary among populations of the redheaded pine sawfly (Neodiprion lecontei): carotenoid-based yellow body color and melanin-based spotting pattern. For both traits, our QTL models explained a substantial proportion of phenotypic variation and suggested a genetic architecture that is neither monogenic nor highly polygenic. Additionally, we used our linkage map to anchor the current N. lecontei genome assembly. With these data, we identified promising candidate genes underlying: (1) a loss of yellow pigmentation in Mid-Atlantic/northeastern populations (Cameo2 and apoLTP-II/I), and (2) a pronounced reduction in black spotting in Great-Lakes populations (yellow, TH, Dat). Several of these genes also contribute to color variation in other wild and domesticated taxa. Overall, our findings are consistent with the hypothesis that predictable genes of large-effect contribute to color evolution in nature.

genetics↗