Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair
Karl P Hodel,
Richard de Borja,
Erin E Henninger,
Brittany B Campbell,
Nathan Ungerleider,
Nicholas Light,
Tong Wu,
Kimberly G LeCompte,
A Yasemin Goksenin,
Bruce A Bunnell,
Uri Tabori,
Adam Shlien,
Zachary F Pursell
Affiliations
Karl P Hodel
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
Richard de Borja
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
Erin E Henninger
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
Brittany B Campbell
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada
Nathan Ungerleider
Department of Pathology, Tulane University School of Medicine, New Orleans, United States
Nicholas Light
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
Tong Wu
Department of Pathology, Tulane University School of Medicine, New Orleans, United States
Kimberly G LeCompte
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
A Yasemin Goksenin
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
Bruce A Bunnell
Department of Pharmacology, Tulane University School of Medicine, New Orleans, United States; Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, United States
Uri Tabori
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada; Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Canada
Adam Shlien
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States
Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε.