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

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 toxi

SUBMITTER: Hwang T 

PROVIDER: S-EPMC11724276 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature