Volume 227, Issue 3, July 2024

Gamma secretase executes the final activating step in Notch signal transduction. Its four conserved subunits are thought to be essential. Here the authors discover the first example of Notch signaling without the APH-2/Nicastrin subunit. The surprising dispensability of APH-2/Nicastrin in C. elegans germ cells contrasts with its essential role in the C. elegans embryo. The authors propose a revised model of gamma secretase in which APH-2/Nicastrin acts only to increase gamma secretase activity, and therefore, in some cellular contexts is unnecessary.

The authors identified genetic and biochemical interactions in baker’s yeast between Mlh1-Mlh3, which acts in meiotic crossover resolution, and Dmc1, the recombinase responsible for recombination between homologous chromosomes during meiosis. Partial complementation of Mlh3 crossover functions was observed when MLH3 expression was restricted to roughly the time of crossover resolution, suggesting that Mlh3 function can be provided late in meiotic prophase at some functional cost. A model for how Dmc1 could facilitate Mlh1-Mlh3’s role in crossover resolution is presented.

UV damage in mitochondrial genomes has been historically difficult to study. One potential solution is excision repair sequencing (XR-seq), where UV damaged molecules are captured and directly sequenced. The authors analysis of the mitochondrial derived reads in numerous publicly available XR-seq datasets provides valuable insights into the fate of photodamage in mitochondrial genomes. They show that in diverse eukaryotes, mitochondrially derived DNA fragments of characteristic length and nucleotide composition are produced following UV exposure, possibly from mtDNA degradation or repair.

Both genetic and non-genetic factors influence an individual's risk of coronary artery disease and prediction models that combine these contributors to risk are well studied. In this paper the authors first show that existing models that perform well at the level of the individual are not well suited for predicting disease rates in groups of people based on geographical location. They explore the reasons for this surprising result and introduce a novel model that works well.