CCAR1 PROMOTES DNA REPAIR VIA ALTERNATIVE SPLICING – PUBLISHED IN MOLECULAR CELL

Cells constantly experience DNA damage throughout their lifespan due to a variety of endogenous and exogenous factors. Among the different types of DNA damage, double-stranded breaks (DSBs) are particularly severe and can be detrimental if left unrepaired. Eukaryotes have developed mechanisms to detect and repair such damage, known as the DNA damage response (DDR), which involves hundreds of key players and supporting factors. Are you curious to discover more about DDR? Have a look at latest breakthrough,  led by postdoc Erman Karasu in a collaboration with the Jonas group (IMBB) and Zavolan group (University of Basel).

By utilizing a CRISPR screening system to assay about 18,000 gene knockdowns, we identified new players influencing homology-directed repair (HDR). Among these, we focused on CCAR1, an enigmatic gene whose role in the DDR was not well understood. We found that reducing CCAR1 levels impaired both HDR and the repair of interstrand crosslinks, similar to what occurs when the Fanconi anemia (FA) pathway is inactivated. Interestingly, CCAR1 deficiency leads to FANCA protein depletion without affecting FANCA mRNA or other FA gene mRNAs levels. Instead, CCAR1 ensures FANCA mRNA splicing by suppressing a poison exon inclusion. CCAR1 binds to U2-type spliceosome and acts on multiple splicing sites. This demonstrates that CCAR1 is crucial for proper mRNA splicing. Further analysis showed that CCAR1’s role in mRNA splicing extends beyond FANCA, affecting many genes and ensuring that their mRNAs are correctly processed in both mouse and human cells. Our work highlights CCAR1’s unexpected role in maintaining accurate mRNA splicing, which is essential for proper protein function.

For more info check out our new paper in Molecular Cell!