Genetic compensation responses (GCRs) can be induced by deleterious mutations in living organisms in order to maintain genetic robustness. One type of GCRs, homology-dependent GCR (HDGCR), involves transcriptional activation of one or more homologous genes related to the mutated gene. In zebrafish, ~80% of the genetic mutants produced by gene editing technology failed to show obvious phenotypes. The HDGCR has been proposed to be one of the main reasons for this phenomenon. It is triggered by mutant mRNA bearing a premature termination codon and has been suggested to depend on components of both the nonsense mRNA-mediated degradation (NMD) pathway and the complex of proteins associated with Set1 (COMPASS). However, exactly which specific NMD factor is required for HDGCR remains disputed. Here, zebrafishleg1deleterious mutants are adopted as a model to distinguish the role of the NMD factors Upf1 and Upf3a in HDGCR. Four single mutant lines and three double mutant lines were produced. The RNA-seq data from 71 samples and the ULI-NChIP-seq data from 8 samples were then analyzed to study the HDGCR inleg1mutants. Our results provide strong evidence that Upf3a, but not Upf1, is essential for the HDGCR induced by nonsense mutations inleg1genes where H3K4me3 enrichment appears not to be a prerequisite. We also show that Upf3a is responsible for correcting the expression of hundreds of genes that would otherwise be dysregulated in theleg1deleterious mutant.