NEIL1 and NEIL2 have a dual DNA glycosylase and beta/delta lyase activity. The AP (apurinic/apyrimidinic) site-directed lyase activity of NEIL1 and NEIL2 is their major physiological role, as they can act on AP sites generated spontaneously or by other DNA glycosylases. NEIL1 or NEIL2 cleave the damaged DNA strand 5' to the AP site, producing a 3' phosphate terminus (3'Pi) and a 5' deoxyribose phosphate terminus (5'dRP). DNA polymerase beta (POLB) excises 5'dRP residue but is unable to add the replacement nucleotide to DNA with the 3'Pi end. PNKP, a DNA 3' phosphatase, removes 3'Pi and enables POLB to incorporate the replacement nucleotide, which is followed by ligation of repaired DNA strand by XRCC1:LIG3 complex (Whitehouse et al. 2001, Wiederhold et al. 2004, Das et al. 2006).