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Updated: Jul 19, 2025
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Genome-wide Determination of Mammalian Replication Timing by DNA Content Measurement
Published on: January 19, 2017
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Both cell autonomous and non-autonomous processes modulate the association between replication timing and mutation
Oriya Vardi-Yaacov1, Adar Yaacov1,2,3, Shai Rosenberg2,3
1Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Scientific Reports
|August 12, 2023
Summary
Cancer somatic mutations are influenced by DNA replication timing. Some tumors show a weak link between replication timing and mutation rate, indicating unique mutational processes and potential immune system involvement.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Cancer somatic mutations arise from various DNA mutational and repair processes.
- Mutation rates (MR) are generally higher in late replication timing (RT) regions.
- However, other biological processes can modulate the association between RT and MR.
Purpose of the Study:
- To systematically analyze the mutational landscape across diverse cancer types.
- To investigate the factors influencing the association between replication timing and mutation rate.
- To identify unique characteristics of tumors exhibiting a weak RT-MR association.
Main Methods:
- Analysis of somatic mutations in 2787 tumors from 32 distinct tumor types.
- Systematic examination of the mutational landscape and its correlation with replication timing.
- Comparative analysis of mutational signatures, gene mutations, and gene expression profiles.
Main Results:
- Approximately one-third of analyzed tumor samples displayed a weak association between replication timing and mutation rate.
- These weak association samples exhibited distinct mutational signatures.
- Enrichment of mutations in DNA replication, DNA repair, and chromatin structure genes was observed in weak association tumors.
- Differentially expressed genes in weak association tumors were linked to cell-cell communication and immune system pathways.
Conclusions:
- A subset of tumors deviates from the expected RT-MR association, driven by unique mutational processes.
- Tumors with weak RT-MR association show distinct genetic alterations and gene expression patterns.
- The enrichment of immune and cell-cell communication genes suggests a non-autonomous DNA damage response in these tumors.
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