Exonuclease 1 is part of a DNA repair system that functions to maintain genomic integrity. Exo1 removes mutations in DNA that can occur during replication, recombination and through DNA damaging agents. While the biochemical role of EXO1 had previously been examined in yeast and mammalian cell extracts, its biological role remained a mystery. Interestingly, other researchers had shown that patients with Human Nonpolyposis Colorectal Cancer (HNPCC) and atypical HNPCC had germline variations in the EXO1 gene, suggesting a role for EXO1 in this type of cancer.
To directly test the role of EXO1 in cancer, Dr. Edelmann and colleagues generated mice with an inactivating mutation in the Exo1 gene. Mice lacking Exo1 function had a reduced life span and the surviving mutant mice were twice as likely as their normal counterparts to develop tumors, primarily lymphomas. This suggests a role for EXO1 in maintaining the genome to prevent mutations that could eventually lead to cancer.
In addition to the role in preventing cancer predisposition, analyses of these mice uncovered an important role for Exo1 in fertility. Disruption of Exo1 in males results in severely depleted sperm levels, non-motile sperm and widespread germ cell aneuploidy. Dr. Edelmann and colleagues went on to show that Exo1 is essential for both male and female germ cell meiosis in mice. Dr. Edelmann and Dr. Paula Cohen, also at the Albert Einstein College of Medicine, believe that these results implicate a potential role for EXO1 in human infertility as they state "mutations in this gene can cause infertility by disrupting the process of equal chromosomal segregation necessary for production of genetically viable eggs and sperm".
This study provides the first description of the biological role of a late stage DNA mismatch repair gene and provides interesting insight into the role of this repair machinery in cancer and fertility. The work also exemplifies how advances in our understanding of how cells repair DNA damage, from the early stages of damage recognition, to the late stages of excision and repair, may provide important insights into the role of this machinery in human cancer.
Journal
Genes & Development