Biomedical Research - The NOMIS Foundation

DNA repair is directly performed by hundreds of core factors and indirectly regulated by thousands of others. We massively expanded a CRISPR inhibition and Cas9-editing screening system to discover factors indirectly modulating homology-directed repair (HDR) in the context of ∼18,000 individual gene knockdowns. We focused on CCAR1, a poorly understood gene that we found the depletion of reduced both HDR and interstrand crosslink repair, phenocopying the loss of the Fanconi anemia pathway. CCAR1 loss abrogated FANCA protein without substantial reduction in the level of its mRNA or that of other FA genes. We instead found that CCAR1 prevents inclusion of a poison exon in FANCA. Transcriptomic analysis revealed that the CCAR1 splicing modulatory activity is not limited to FANCA, and it instead regulates widespread changes in alternative splicing that would damage coding sequences in mouse and human cells. CCAR1 therefore has an unanticipated function as a splicing fidelity factor.

The glaciers on Africa’s ‘Mountains of the Moon’ (Rwenzori National Park, Uganda) are predicted to disappear within the next decades owing to climate change. Consequently, the glacier-fed streams (GFSs) that drain them will vanish, along with their resident microbial communities. Despite the relevance of microbial communities for performing ecosystem processes in equatorial GFSs, their ecology remains understudied. Here, we show that the benthic microbiome from the Mt. Stanley GFS is distinct at several levels from other GFSs. Specifically, several novel taxa were present, and usually common groups such as Chrysophytes and Polaromonas exhibited lower relative abundances compared to higher-latitude GFSs, while cyanobacteria and diatoms were more abundant. The rich primary producer community in this GFS likely results from the greater environmental stability of the Afrotropics, and accordingly, heterotrophic processes dominated in the bacterial community. Metagenomics revealed that almost all prokaryotes in the Mt. Stanley GFS are capable of organic carbon oxidation, while greater than 80% have the potential for fermentation and acetate oxidation. Our findings suggest a close coupling between photoautotrophs and other microbes in this GFS, and provide a glimpse into the future for high-latitude GFSs globally where primary production is projected to increase with ongoing glacier shrinkage. © 2023 The Authors.

Publications in Biomedical Research by NOMIS researchers

CCAR1 promotes DNA repair via alternative splicing

The dark side of the moon: First insights into the microbiome structure and function of one of the last glacier-fed streams in Africa