The emerging role of LSm4 RNA-binding protein in DNA double-strand break repair

The human genome is under continuous attack from a variety of endogenous and exogenous DNA-damaging agents that generate various types of DNA lesions. To cope with these lesions and preserve genomic stability, the cells have developed a sophisticated DNA-damage response (DDR) network, consisting of multitude of proteins that sense the damage, transduce signals into cells and execute various cellular responses, including DNA repair. Double-strand breaks (DSBs) are considered the most cytotoxic forms of DNA lesions, as a single unrepaired DSB can trigger cell death or cellular transformation. Vertebrate cells use four DSB repair pathways: homologous recombination (HR); classical nonhomologous end-joining (c-NHEJ); alternative end-joining (alt-EJ) and single-strand annealing (SSA). The mechanisms regulating DSB repair choice remain elusive and require further investigations. Here, we identified a novel function of the Sm-like 4 factor, LSm4, in DDR. While LSm4 protein plays a role in mRNA decapping and pre-mRNA splicing, we showed that LSm4 protein is recruited to DSB sites in a PARP1-dependent manner. Consequently, we demonstrated that LSm4 promotes HR and counteracts NHEJ and its depletion leads to substantial increase in gH2AX levels. Moreover, we revealed that LSm4 regulates the levels of R-loops at DSB sites by a yet unknown mechanism. Taken together, our results identified LSm4 as a novel regulator of DSB repair pathway choice.