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PNAS Papers on HR-Defective Cancer Target, Digenic Disease Detection, More

A Ludwig Institute for Cancer Research- and University of California, San Diego-led team explores potential cancer targets stemming from homologous recombination defects, focusing in on a DNA repair-related flap endonuclease 1 enzyme encoded by the FEN1 genes. Following from findings of a Saccharomyces cerevisiae budding yeast synthetic lethal screen suggesting ties between FEN1 and genome stability, the researchers found that they could curb the growth of human cell lines containing BRCA1 or BRCA2 alterations by dialing down FEN1 levels with small interfering RNA or small molecule inhibitors targeting the endonuclease — findings they explored further in mouse model and cancer cell line experiments. Based on these and other results, the authors propose a potential role for FEN1 inhibitors in targeting cancers with homologous recombination defects. 

Researchers in the US and Australia take a look at genome size and transposable element expansions, in relation to DNA methylation, in dozens of eukaryotic species. Using whole-genome sequencing and whole-genome bisulfite sequencing data for 53 organisms, the team found that overall genome size tended to track with rising transposable element content, while the proportion of CpG sites tended to dip as genomes stretched out. "[Transposable elements] coexist with their host largely because CpG methylation suppresses their transcription," the authors note, reasoning that deamination-related cytosine-to-thymine mutations tend to increase in the presence of cytosine methylation, eventually leading to CpG loss. Consequently, they say, "methylation of [transposable element] DNA allows for genome expansion and also leads to new opportunities for gene control by [transposable element]-based regulatory sites."

A team from France and the US present an approach for detecting digenic disease inheritance — involving two genetic loci — using exome sequence data from an affected individual alone. This case-only strategy searches for gene-by-gene interactions related to traits and diseases using each gene as a unit for analysis, the researchers say. "Our approach is based on the aggregation of rare variants within a gene as the unit of analysis," they write, "addressing the lack of power inherent to studies of rare variants." When they used this approach to search for genetic contributors to a condition called craniosynostosis using an exome sequence set generated for a prior study, for example, the authors detected digenic inheritance of the birth defect, consistent with past reports.