HAX-1 is a multifunctional protein involved in the regulation of apoptosis, cell motility and calcium homeostasis. It is also reported to bind RNA: it associates with structural motifs present in the 3' untranslated regions of at least two different transcripts, but the functional significance of this binding remains unknown. Although HAX-1 has been detected in various cellular compartments, it is predominantly cytoplasmic. Our detailed localization studies of HAX-1 isoforms revealed partial nuclear localization, the extent of which depends on the protein isoform. Further studies demonstrated that HAX-1 is in fact a nucleocytoplasmic shuttling protein, dependent on the XPO1 nuclear export receptor. Systematic mutagenesis allowed identification of the two nuclear export signals in the HAX-1 sequence. HAX-1 nuclear accumulation was observed after inhibition of nuclear export by leptomycin B, but also after specific cellular stress. The biological role of HAX-1 nuclear localization and shuttling remains to be established, but HAX-1 transcript-binding properties suggest that it might be connected to mRNA processing and surveillance. In this study HAX-1 status was shown to influence mRNA levels of DNA polymerase beta, one of the HAX-1 mRNA targets, although this effect becomes pronounced only after specific stress is applied. Moreover, HAX-1 tethering to the reporter transcript caused a significant decrease in its expression. Additionally, reported here HAX-1 co-localization with P-body markers also implies its role in mRNA processing. These results suggest that HAX-1 might be involved in the regulation of expression of the bound transcripts, possibly, as part of the stress response. © 2012 The Authors Journal compilation © 2012 FEBS.