Molecular origins of mutational spectra produced by the environmental carcinogen N-nitrosodimethylamine and SN1 chemotherapeutic agents

Amanda L. Armijo, Pennapa Thongaram, Bogdan I. Fedeles, Judy Yau, Jennifer E Kay, Joshua J. Corrigan, Marisa Chancharoen, Supawadee Chawanthayatham, Leona D. Samson, Sebastian E. Carrasco, Bevin P. Engelward, James G. Fox, Robert G. Croy & John M. Essigmann

DNA-methylating environmental carcinogens such as N-nitrosodimethylamine (NDMA) and certain alkylators used in chemotherapy form O6-methylguanine (m6G) as a functionally critical intermediate. NDMA is a multi-organ carcinogen found in contaminated water, polluted air, preserved foods, tobacco products, and many pharmaceuticals. Only ten weeks after exposure to NDMA, neonatally-treated mice experienced elevated mutation frequencies in liver, lung and kidney of ~35-fold, 4-fold, and 2-fold, respectively. High-resolution mutational spectra (HRMS) of liver and lung revealed distinctive patterns dominated by GCAT mutations in 5’-Pu-G-3’ contexts, very similar to human COSMIC mutational signature SBS11. Commonly associated with alkylation damage, SBS11 appears in cancers treated with the DNA alkylator temozolomide (TMZ). When cells derived from the mice were treated with TMZ, N-nitroso-N-methylnitrosourea, and streptozotocin (two other therapeutic methylating agents), all displayed NDMA-like HRMS, indicating mechanistically convergent mutational processes. The role of m6G in shaping the mutational spectrum of NDMA was probed by removing MGMT, the main cellular defense against m6G. MGMT-deficient mice displayed a strikingly enhanced mutant frequency, but identical HRMS, indicating that the mutational properties of these alkylators is likely owed to sequence-specific DNA binding. In sum, the HRMS of m6G-forming agents constitute an early-onset biomarker of exposure to DNA methylating carcinogens and drugs.

DOI: None

Zenodo URL: None

Created at: 31st Mar 2023 at 15:02

Contents

Illumina Sequencing - Data Linked

No description specified

DNA-samples-publish2023-03-08_13-15.xlsx

Batch sample publishing

  • DNA-SEQ-samples-publish2023-03-08_13-15.xlsx

D.SEQ-samples-publish2023-03-24_13-17.xlsx

Batch sample publishing

  • D.SEQ-samples-publish2023-03-24_13-17.xlsx

P.ESS-230308-V2_Duplex-sequencing.docx

No description specified

  • P.ESS-230308-V2_Duplex-sequencing.docx.docx

Necropsy - Metadata

No description specified

MUS-samples-publish2023-03-08_12-23.xlsx

Batch sample publishing

  • MUS-samples-publish2023-03-08_12-23.xlsx

PAV-samples-publish2023-03-08_12-32.xlsx

Batch sample publishing

  • PAV-samples-publish2023-03-08_12-32.xlsx

TIS-samples-publish2023-03-08_12-40.xlsx

Batch sample publishing

  • TIS-samples-publish2023-03-08_12-40.xlsx

Extraction and Library Creation - Metadata

No description specified

CEL-samples-publish2023-03-08_11-57.xlsx

Batch sample publishing

  • CEL-samples-publish2023-03-08_11-57.xlsx

TIS-samples-publish2023-03-08_12-40.xlsx

Batch sample publishing

  • TIS-samples-publish2023-03-08_12-40.xlsx

DNA-samples-publish2023-03-08_13-15.xlsx

Batch sample publishing

  • DNA-samples-publish2023-03-08_13-15.xlsx

P.ESS-230303-V2_Cell-culture.docx

No description specified

  • P.ESS-230303-V2_Cell-culture.docx.docx

P.ENG-200831-V1_NDMA-Juvenile-Mouse-Injection-Protocol.pdf

No description specified

  • NDMA-Juvenile-Mouse-Injection-Protocol (2).pdf

P.ENG-200806-V2_Short-Term-Collection-at-Necropsy.pdf

No description specified

  • Short-Term-Collection-at-Necropsy.pdf

P.ENG-220105-V1_NDMA-Juvenile-Mouse-Single-Injection-Protocol.docx

No description specified

  • NDMA-Juvenile-Mouse-Single-Injection-Protocol.docx

P.ENG-220105-V1_Tissue-Collection-at-Necropsy-(2021).docx

No description specified

  • Tissue Collection at Necropsy (2021).docx

GPT Assay - Data Attached

No description specified

DNA-samples-publish2023-03-08_13-15.xlsx

Batch sample publishing

  • DNA-GPT-samples-publish2023-03-08_13-15.xlsx

NDMA_in-vivo_gpt_data.xlsx

No description specified

  • NDMA_in-vivo_gpt_data.xlsx

D.GPT-samples-publish2023-03-08_13-55.xlsx

Batch sample publishing

  • D.GPT-samples-publish2023-03-08_13-55.xlsx

P.ESS-201123-V1_gpt-NextGen-Protocol-.pdf

No description specified

  • P.ESS-201123-V1_gpt-NextGen-Protocol-.pdf.pdf

Genome Alignment - Data Linked

No description specified

D.SEQ-samples-publish2023-03-24_13-17.xlsx

Batch sample publishing

  • D.SEQ-samples-publish2023-03-24_13-17.xlsx

A.ALN-samples-publish2023-03-24_14-05.xlsx

Batch sample publishing

  • samples-publish2023-03-24_14-05.xlsx

P.ESS-230303-V1_Data-processing-(alignment).docx

No description specified

  • Data processing (alignment).docx

Mutational Spectral Analysis - Data Attached

No description specified

Armijo-NDMA_HRMS-data.xlsx

No description specified

  • Armijo-NDMA_HRMS-data.xlsx

A.MUSP-samples-publish2023-03-08_17-46.xlsx

Batch sample publishing

  • A.MUSP-samples-publish2023-03-08_17-4 - Copy.xlsx

P.ESS-230303-V1_Data-processing-(alignment).docx

No description specified

  • Data processing (alignment).docx
Fingerprints

These checksums allow you to check a Snapshot you have downloaded hasn't been modified. For details on how to use these please visit this guide

MD5: 1e8cb389993e49ed28ce3aa9edc7b093

SHA1: 83e2ee7b97da9a2847dfd64cb54baa0a68aff541

Snapshots
Snapshot 1 (31st Mar 2023)
Activity

Views: 301   Downloads: 1

Created: 31st Mar 2023 at 15:02

Powered by
(v.1.14.2)
Copyright © 2008 - 2023 The University of Manchester and HITS gGmbH