Multi-functions of exonuclease 1 in DNA damage response and cancer susceptibility

Exonuclease 1 (EXO1) can catalyze nucleotide chain excision with its conserved N-terminal domain of 5′ to 3′ exonuclease activity, enabling it to influence diverse biological processes facing the challenges of genotoxic environmental factors such as ionizing radiation. This nuclease activity enables EXO1 to maintain replication forks and telomeres length, to facilitate post-replication DNA repair and to process the end resection step of homologous recombination of DNA double-strand breaks-induced by ionizing radiation. When DNA replication is disrupted or blocked, EXO1 can cleave the broken DNA ends to form 3’ ssDNA, leading to repair pathways activation. Excess EXO1-mediated nucleotide excision, however, can introduce an abundance of single-stranded DNA that can cause mutation and recombination via micro-homology-mediated end joining or single-strand annealing mechanisms, contributing to a loss of genetic information. EXO1 activity must therefore be carefully regulated within healthy cells. The mutations and dysregulations of EXO1 can increase the sensitivity of cells to radiation injury and risk of oncogenic transformation, limit the adoption of specific treatments in a range of human diseases. As such, EXO1 represents a promising target for the treatment and prevention of cancer. In the present review, we delineate the structural properties and functional characteristics of EXO1, discuss the relationship between this exonuclease and cancer susceptibility as well as the second cancers related to radiotherapy.