The DNA repair protein NEIL3 has DNA glycosylase activity, removing oxidised bases from DNA and is expressed mainly during the S and G2 phases of the cell cycle, indicating a role in DNA replication. We have recently shown that NEIL1 and NEIL3 can also unhook interstrand cross-links (ICLs) in three- and four-stranded DNA structures that may arise due to DNA replication fork bypass of an ICL. Uniquely, NEIL3 targets both DNA strands without generating a single-strand break, thus avoiding the DNA damage response. We would like to follow up these biochemical experiments by studying the ability of human NEIL3 to complement the loss of ICL repair that is a hallmark of Fanconi Anaemia (FA) cells. This will be achieved, in part, using mammalian expression vectors to express NEIL3 and conversely siRNA/gene editing to decrease endogenous NEIL3 in a panel of FA cells and determining their sensitivity to cross-link inducing agents. These experiments will help to elucidate the role of NEIL3 in vivo and the part it may play in the resistance to clinically relevant cross-linking agents that are used in cancer chemotherapy.
Further details: We have active collaborations with groups in Liverpool, UK and France.