Pseudokinase HPO-11 inhibits nonsense-mediated decay to ensure genome stability in C. elegans

DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can induce mutations and chromosome rearrangement therefore causing genome instability (GIN). In response to DSBs, cells activate the DNA damage response by hierarchical assembly of signaling and repair mechanisms. This involves recruitment of the repair factors at DSB sites, local chromatin remodeling, cell cycle arrest and, eventually, DNA repair or apoptosis. Studies investigating mechanisms ensuring genome stability have so far mostly focused on DNA-protein interactions and signal transduction in response to DNA damage. Emerging evidence in the last decade suggests that post-transcriptional control of gene expression by RNA-binding proteins also participates in maintaining genome integrity. However, how specific control of RNA fate mechanistically affects genome stability is still poorly understood. Here, we report that the pseudokinase HPO-11 ensures genome integrity in C. elegans. Loss of hpo-11 leads to accumulation of R-loops, increased DSBs and germline apoptosis, as well as an elevated mutation rate in the somatic cells. In addition, inhibition of nonsense mediated decay (NMD) reduces DSBs and germline apoptosis in the absence of hpo-11. We find that HPO-11 physically interacts with SMG-2, the core factor of NMD, and prevents degradation of specific transcripts by NMD, thus contributing to maintenance of genome stability. Furthermore, knock-down of hpo-11 human homologs NRBP1/2 also results in increased DNA DSBs, and NRBP1/2 physically interact with the human SMG-2 orthologue UPF1. In summary, our work identifies an evolutionarily conserved role of HPO-11 to protect genome stability via suppressing abnormal mRNA decay by NMD.