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Human DNA polymerase iota (poli) is a unique member of the Y-family of specialised polymerases that displays a 5 0 deoxyribose phosphate (dRP) lyase activity. Although poli is well conserved in higher eukaryotes, its role in mammalian cells remains unclear. To investigate the biological importance of poli in human cells, we generated fibroblasts stably downregulating poli (MRC5-poli KD ) and examined their response to several types of DNA-damaging agents. We show that cell lines downregulating poli exhibit hypersensitivity to DNA damage induced by hydrogen peroxide (H 2 O 2 ) or menadione but not to ethylmethane sulphonate (EMS), UVC or UVA. Interestingly, extracts from cells downregulating poli show reduced base excision repair (BER) activity. In addition, poli binds to chromatin after treatment of cells with H 2 O 2 and interacts with the BER factor XRCC1. Finally, green fluorescent protein-tagged poli accumulates at the sites of oxidative DNA damage in living cells. This recruitment is partially mediated by its dRP lyase domain and ubiquitin-binding domains. These data reveal a novel role of human poli in protecting cells from oxidative damage.