Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

eLife

Nathan Ungerleider¹  Adam Shlien²  A Yasemin Goksenin³  Bruce A Bunnell³  Karl P Hodel³  Erin E Henninger³  Kimberly G LeCompte⁴  Nicholas Light⁴  Uri Tabori⁵  Zachary F Pursell⁶  Tong Wu⁶  Richard de Borja⁶  Brittany B Campbell⁷ 

[1] Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada;Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, United States;Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States;Department of Pathology, Tulane University School of Medicine, New Orleans, United States;Department of Pharmacology, Tulane University School of Medicine, New Orleans, United States;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;

关键词: Genome Stability;    Mutagenesis;    DNA Replication;    DNA Polymerase;   

DOI  :  10.7554/eLife.32692

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown