Comprehensive whole-genome sequencing reveals origins of mutational signatures associated with aging, mismatch repair deficiency and temozolomide chemotherapy.

in Nucleic acids research by Taejoo Hwang, Lukasz Karol Sitko, Ratih Khoirunnisa, Fernanda Navarro-Aguad, David M Samuel, Hajoong Park, Banyoon Cheon, Luthfiyyah Mutsnaini, Jaewoong Lee, Burçak Otlu, Shunichi Takeda, Semin Lee, Dmitri Ivanov, Anton Gartner

TLDR

  • A study of TMZ-induced mutational signatures in DNA repair-deficient cell lines reveals potential vulnerabilities of TMZ-resistant tumors, highlighting the importance of understanding the molecular mechanisms of chemotherapy resistance.

Abstract

In a comprehensive study to decipher the multi-layered response to the chemotherapeutic agent temozolomide (TMZ), we analyzed 427 genomes and determined mutational patterns in a collection of ∼40 isogenic DNA repair-deficient human TK6 lymphoblast cell lines. We first demonstrate that the spontaneous mutational background is very similar to the aging-associated mutational signature SBS40 and mainly caused by polymerase zeta-mediated translesion synthesis (TLS). MSH2-/- mismatch repair (MMR) knockout in conjunction with additional repair deficiencies uncovers cryptic mutational patterns. We next report how distinct mutational signatures are induced by TMZ upon sequential inactivation of DNA repair pathways, mirroring the acquisition of chemotherapy resistance by glioblastomas. The most toxic adduct induced by TMZ, O6-meG, is directly repaired by the O6-methylguanine-DNA methyltransferase (MGMT). In MGMT-/- cells, MMR leads to cell death and limits mutagenesis. MMR deficiency results in TMZ resistance, allowing the accumulation of ∼105 C > T substitutions corresponding to signature SBS11. Under these conditions, N3-methyladenine (3-meA), processed by base excision repair (BER), limits cell survival. Without BER, 3-meA is read through via error-prone TLS, causing T > A substitutions but not affecting survival. Blocking BER after abasic site formation results in large deletions and TMZ hypersensitization. Our findings reveal potential vulnerabilities of TMZ-resistant tumors.

Overview

  • The study analyzed 427 genomes of isogenic DNA repair-deficient human TK6 lymphoblast cell lines to understand the multi-layered response to temozolomide (TMZ) chemotherapy.
  • The researchers used a combination of polymerase zeta-mediated translesion synthesis (TLS) and mismatch repair (MMR) knockout to uncover cryptic mutational patterns and TMZ-induced mutational signatures.
  • The study aimed to understand the development of chemotherapy resistance in glioblastomas and identify potential vulnerabilities in TMZ-resistant tumors.

Comparative Analysis & Findings

  • The study found that the spontaneous mutational background is similar to the aging-associated mutational signature SBS40, mainly caused by polymerase zeta-mediated translesion synthesis.
  • Distinct mutational signatures were induced by TMZ upon sequential inactivation of DNA repair pathways, mirroring the acquisition of chemotherapy resistance by glioblastomas.
  • The study identified potential vulnerabilities of TMZ-resistant tumors, including the accumulation of C > T substitutions and N3-methyladenine-mediated cell death.

Implications and Future Directions

  • The findings have implications for understanding the development of chemotherapy resistance in glioblastomas and identifying potential targets for therapy.
  • Future studies could investigate the use of TMZ in combination with other agents to enhance its effectiveness against TMZ-resistant tumors.
  • The study also highlights the importance of understanding the molecular mechanisms of TMZ resistance to develop effective personalized treatment strategies.
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