Lineage-specific amino acids define functional attributes of the protomer-protomer interfaces for the Rad51 and Dmc1 recombinases.

Most eukaryotes possess two Rad51/RecA family DNA recombinases that are thought to have arisen from an ancient gene duplication event: Rad51, which is expressed in both mitosis and meiosis; and Dmc1, which is only expressed in meiosis. To explore the evolutionary relationship between these recombinases, here, we present high-resolution CryoEM structures of Rad51 filaments and Dmc1 filaments bound to ssDNA, which reveal a pair of stacked interfacial aromatic amino acid residues that are nearly universally conserved in Rad51 but are absent from Dmc1. We use a combination of bioinformatics, genetic analysis of natural sequence variation, and deep mutational analysis to probe the functionally tolerated sequence space for these stacked aromatic residues.

ATF4 regulates mitochondrial dysfunction, mitophagy, and autophagy, contributing to corneal endothelial apoptosis under chronic ER stress in Fuchs' dystrophy.

Purpose: Endoplasmic reticulum (ER) stress, mitochondrial dysfunction, mitophagy/autophagy are known to contribute independently to corneal endothelial (CE) apoptosis in Fuchs' endothelial corneal dystrophy (FECD). However, the role of a well-studied specific ER stress pathway (PERK-ATF4-CHOP) in regulating mitochondrial dysfunction, mitophagy/autophagy, and apoptosis is unknown. The purpose of this study is to explore the role of ATF4 in regulating mitochondrial dysfunction and mitophagy/autophagy, leading to CEnC apoptosis in FECD.