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Analysis of gene expression and mutation data points on contribution of transcription to the mutagenesis by APOBEC

Almira Chervova1,2, Bulat Fatykhov3, Alexander Koblov4

  • 1Institute of Oncology, Radiology and Nuclear Medicine, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia.

NAR Cancer
|July 28, 2021
PubMed

Insights

APOBEC enzymes drive cancer mutations through DNA replication and transcription. This study quantifies their relative impact, finding transcription significantly influences APOBEC mutagenesis, especially in highly expressed genes.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • APOBEC enzymes are implicated in human cancer mutagenesis.
  • The precise mechanisms driving APOBEC mutagenesis, particularly the roles of DNA replication and transcription, are not fully understood.

Purpose of the Study:

  • To investigate and compare the contributions of DNA replication and transcription to APOBEC-mediated mutagenesis in human cancers.
  • To analyze gene expression and whole genome sequencing data to elucidate these mechanisms.

Main Methods:

  • Analysis of gene expression and whole genome sequencing data from five human cancer types with high APOBEC activity.
  • Identification of APOBEC mutation signatures (TCN motif).
  • Correlation analysis between mutation density, replication timing, and gene expression levels.

Main Results:

  • A correlation between active APOBEC mutagenesis and gene expression was observed.
  • APOBEC-induced mutations were increased in early-replicating DNA regions.
  • The density of APOBEC mutations was higher on the sense strand, correlating positively with gene expression levels.

Conclusions:

  • Transcription plays a significant role in APOBEC mutagenesis, comparable to replication.
  • Gene expression levels directly influence the density of APOBEC-induced mutations.
  • Understanding these factors is crucial for targeting APOBEC-driven cancers.

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