Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair
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 com...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2018-02-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/32692 |
| _version_ | 1811201664038731776 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Karl P Hodel |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:24:39Z |
| format | Article |
| id | doaj.art-b21959d54c17454baf2f9fe1bada282c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:24:39Z |
| publishDate | 2018-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-b21959d54c17454baf2f9fe1bada282c2022-12-22T03:52:01ZengeLife Sciences Publications LtdeLife2050-084X2018-02-01710.7554/eLife.32692Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repairKarl P Hodel0Richard de Borja1Erin E Henninger2Brittany B Campbell3Nathan Ungerleider4Nicholas Light5Tong Wu6Kimberly G LeCompte7A Yasemin Goksenin8Bruce A Bunnell9Uri Tabori10Adam Shlien11Zachary F Pursell12https://orcid.org/0000-0001-5871-7192Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United StatesProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, CanadaDepartment of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United StatesThe 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, CanadaDepartment of Pathology, Tulane University School of Medicine, New Orleans, United StatesProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, CanadaDepartment of Pathology, Tulane University School of Medicine, New Orleans, United StatesDepartment of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United StatesDepartment of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United StatesDepartment 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 StatesProgram 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, CanadaProgram 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, CanadaDepartment 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 StatesTumors 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.https://elifesciences.org/articles/32692Genome StabilityMutagenesisDNA ReplicationDNA Polymerase |
| spellingShingle | 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 Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair eLife Genome Stability Mutagenesis DNA Replication DNA Polymerase |
| title | Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair |
| title_full | Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair |
| title_fullStr | Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair |
| title_full_unstemmed | Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair |
| title_short | Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair |
| title_sort | explosive mutation accumulation triggered by heterozygous human pol ε proofreading deficiency is driven by suppression of mismatch repair |
| topic | Genome Stability Mutagenesis DNA Replication DNA Polymerase |
| url | https://elifesciences.org/articles/32692 |
| work_keys_str_mv | AT karlphodel explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT richarddeborja explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT erinehenninger explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT brittanybcampbell explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT nathanungerleider explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT nicholaslight explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT tongwu explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT kimberlyglecompte explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT ayasemingoksenin explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT bruceabunnell explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT uritabori explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT adamshlien explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair AT zacharyfpursell explosivemutationaccumulationtriggeredbyheterozygoushumanpoleproofreadingdeficiencyisdrivenbysuppressionofmismatchrepair |