A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

Supplemental information: Document S1. Figures S1–S5, Tables S1–S3, and Methods S1 available at: https://www.cell.com/cms/10.1016/j.chembiol.2021.02.006/attachment/3e31e265-54fc-4337-ac40-861ecb85706e/mmc1.pdf (1.44 MB)Copyright © 2021 The Authors. BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a Kd of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-methylbenzyl group occupies the Ala-binding pocket. In cells, CAM833 diminishes formation of damage-induced RAD51 nuclear foci; inhibits RAD51 molecular clustering, suppressing extended RAD51 filament assembly; potentiates cytotoxicity by ionizing radiation, augmenting 4N cell-cycle arrest and apoptotic cell death and works with poly-ADP ribose polymerase (PARP)1 inhibitors to suppress growth in BRCA2-wildtype cells. Thus, chemical inhibition of the protein-protein interaction between BRCA2 and RAD51 disrupts HDR and potentiates DNA damage-induced cell death, with implications for cancer therapy.Wellcome Trust Translational Award ( 080083/Z/06/Z ); Seeding Drug Discovery Award ( 091058/Z/09/Z ); Medical Research Council (MRC) Program grants MC_UU_12022/1 and MC_UU_12022/8; Astex Pharmaceuticals

Phylogenetic approaches reveal biodiversity threats under climate change

Predicting the consequences of climate change for biodiversity is critical to conservation efforts(1-3). Extensive range losses have been predicted for thousands of individual species(4), but less is known about how climate change might impact whole clades(1) and landscape-scale patterns of biodiversity(5). Here, we show that climate change scenarios imply significant changes in phylogenetic diversity and phylogenetic endemism at a continental scale in Australia using the hyper-diverse clade of eucalypts. We predict that within the next 60 years the vast majority of species distributions (91%) across Australia will shrink in size (on average by 51%) and shift south on the basis of projected suitable climatic space. Geographic areas currently with high phylogenetic diversity and endemism are predicted to change substantially in future climate scenarios. Approximately 90% of the current areas with concentrations of palaeo-endemism(6) (that is, places with old evolutionary diversity) are predicted to disappear or shift their location. These findings show that climate change threatens whole clades of the phylogenetic tree, and that the outlined approach can be used to forecast areas of biodiversity losses and continental-scale impacts of climate change