scholarly journals Characteristics of mutational signatures of unknown etiology

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Xiaoju Hu ◽  
Zhuxuan Xu ◽  
Subhajyoti De
Keyword(s):  
Dna Damage ◽  
Point Mutations ◽  
Gc Content ◽  
Unknown Origin ◽  
Unknown Etiology ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
Disease Etiology ◽  
Repair Processes ◽  
A Genome

Abstract Although not all somatic mutations are cancer drivers, their mutational signatures, i.e. the patterns of genomic alterations at a genome-wide scale, provide insights into past exposure to mutagens, DNA damage and repair processes. Computational deconvolution of somatic mutation patterns and expert curation pan-cancer studies have identified a number of mutational signatures associated with point mutations, dinucleotide substitutions, insertions and deletions, and rearrangements, and have established etiologies for a subset of these signatures. However, the mechanisms underlying nearly one-third of all mutational signatures are not yet understood. The signatures with established etiology and those with hitherto unknown origin appear to have some differences in strand bias, GC content and nucleotide context diversity. It is possible that some of the hitherto ‘unknown’ signatures predominantly occur outside gene regions. While nucleotide contexts might be adequate to establish etiologies of some mutational signatures, in other cases additional features, such as broader (epi)genomic contexts, including chromatin, replication timing, processivity and local mutational patterns, may help fully understand the underlying DNA damage and repair processes. Nonetheless, remarkable progress in characterization of mutational signatures has provided fundamental insights into the biology of cancer, informed disease etiology and opened up new opportunities for cancer prevention, risk management, and therapeutic decision making.

scholarly journals Mutational signatures are jointly shaped by DNA damage and repair

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadezda V. Volkova ◽  
Bettina Meier ◽  
Víctor González-Huici ◽  
Simone Bertolini ◽  
Santiago Gonzalez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Point Mutations ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
C Elegans ◽  
Dna Repair Deficiency ◽  
Dna Alterations ◽  
Repair Pathways

AbstractCells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.

scholarly journals RepairSig: Deconvolution of DNA damage and repair contributions to the mutational landscape of cancer

2020 ◽  
Author(s):  
Damian Wojtowicz ◽  
Jan Hoinka ◽  
Bayarbaatar Amgalan ◽  
Yoo-Ah Kim ◽  
Teresa M. Przytycka
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
Therapeutic Implications ◽  
Mutational Landscape ◽  
Repair Processes ◽  
Cancer Genomes ◽  
Current Paradigm ◽  
Mutational Processes

AbstractMany mutagenic processes leave characteristic imprints on cancer genomes known as mutational signatures. These signatures have been of recent interest regarding their applicability in studying processes shaping the mutational landscape of cancer. In particular, pinpointing the presence of altered DNA repair pathways can have important therapeutic implications. However, mutational signatures of DNA repair deficiencies are often hard to infer. This challenge emerges as a result of deficient DNA repair processes acting by modifying the outcome of other mutagens. Thus, they exhibit non-additive effects that are not depicted by the current paradigm for modeling mutational processes as independent signatures. To close this gap, we present RepairSig, a method that accounts for interactions between DNA damage and repair and is able to uncover unbiased signatures of deficient DNA repair processes. In particular, RepairSig was able to replace three MMR deficiency signatures previously proposed to be active in breast cancer, with just one signature strikingly similar to the experimentally derived signature. As the first method to model interactions between mutagenic processes, RepairSig is an important step towards biologically more realistic modeling of mutational processes in cancer. The source code for RepairSig is publicly available at https://github.com/ncbi/RepairSig.

scholarly journals Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis

2017 ◽  
Author(s):  
Anna R Poetsch ◽  
Simon J Boulton ◽  
Nicholas M Luscombe
Keyword(s):  
Dna Damage ◽  
Oxidative Damage ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Accumulation Rate ◽  
Repetitive Sequences ◽  
Open Chromatin ◽  
Regulatory Sequences ◽  
Dna Damage And Repair ◽  
A Genome

AbstractDNA is subject to constant chemical modification and damage, which eventually results in variable mutation rates throughout the genome. Although detailed molecular mechanisms of DNA damage and repair are well-understood, damage impact and execution of repair across a genome remains poorly defined. To bridge the gap between our understanding of DNA repair and mutation distributions we developed a novel method, AP-seq, capable of mapping apurinic sitesand 8-oxo-7,8-dihydroguanine bases at ∼300bp resolution on a genome-wide scale. We directly demonstrate that the accumulation rate of oxidative damage varies widely across the genome, with hot spots acquiring many times more damage than cold spots. Unlike SNVs in cancers, damage burden correlates with marks for open chromatin notably H3K9ac and H3K4me2. Oxidative damage is also highly enriched in transposable elements and other repetitive sequences. In contrast, we observe decreased damage at promoters, exons and termination sites, but not introns, in a seemingly transcription-independent manner. Leveraging cancer genomic data, we also find locally reduced SNV rates in promoters, genes and other functional elements. Taken together, our study reveals that oxidative DNA damage accumulation and repair differ strongly across the genome, but culminate in a previously unappreciated mechanism that safe-guards the regulatory sequences and the coding regions of genes from mutations.

scholarly journals Genome-Wide Adductomics Analysis Reveals Heterogeneity in the Induction and Loss of Cyclobutane Thymine Dimers across Both the Nuclear and Mitochondrial Genomes

2019 ◽  
Vol 20 (20) ◽  
pp. 5112 ◽  
Author(s):  
Alaa S. Alhegaili ◽  
Yunhee Ji ◽  
Nicolas Sylvius ◽  
Matthew J. Blades ◽  
Mahsa Karbaschi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nuclear Dna ◽  
Mitochondrial Genomes ◽  
Differential Distribution ◽  
Dna Damage And Repair ◽  
Specific Level ◽  
Genome Wide ◽  
A Genome ◽  
High Resolution Map ◽  
Cellular Dna

The distribution of DNA damage and repair is considered to occur heterogeneously across the genome. However, commonly available techniques, such as the alkaline comet assay or HPLC-MS/MS, measure global genome levels of DNA damage, and do not reflect potentially significant events occurring at the gene/sequence-specific level, in the nuclear or mitochondrial genomes. We developed a method, which comprises a combination of Damaged DNA Immunoprecipitation and next generation sequencing (DDIP-seq), to assess the induction and repair of DNA damage induced by 0.1 J/cm2 solar-simulated radiation at the sequence-specific level, across both the entire nuclear and mitochondrial genomes. DDIP-seq generated a genome-wide, high-resolution map of cyclobutane thymine dimer (T<>T) location and intensity. In addition to being a straightforward approach, our results demonstrated a clear differential distribution of T<>T induction and loss, across both the nuclear and mitochondrial genomes. For nuclear DNA, this differential distribution existed at both the sequence and chromosome level. Levels of T<>T were much higher in the mitochondrial DNA, compared to nuclear DNA, and decreased with time, confirmed by qPCR, despite no reported mechanisms for their repair in this organelle. These data indicate the existence of regions of sensitivity and resistance to damage formation, together with regions that are fully repaired, and those for which > 90% of damage remains, after 24 h. This approach offers a simple, yet more detailed approach to studying cellular DNA damage and repair, which will aid our understanding of the link between DNA damage and disease.

scholarly journals Mutational impact and signature of ionizing radiation

2021 ◽  
Author(s):  
Jeonghwan Youk ◽  
Hyun Woo Kwon ◽  
Joonoh Lim ◽  
Eunji Kim ◽  
Ryul Kim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Mammalian Cells ◽  
Single Cells ◽  
Dna Double Strand Breaks ◽  
Structural Variations ◽  
Dna Damage And Repair ◽  
Repair Processes ◽  
Massive Number ◽  
Chaotic Nature

AbstractWhole-genome sequencing (WGS) of human tumors and normal cells exposed to various carcinogens has revealed distinct mutational patterns that provide deep insights into the DNA damage and repair processes. Although ionizing radiation (IR) is conventionally known as a strong carcinogen, its genome-wide mutational impacts have not been comprehensively investigated at the single-nucleotide level. Here, we explored the mutational landscape of normal single-cells after exposure to the various levels of IR. On average, 1 Gy of IR exposure generated ∼16 mutational events with a spectrum consisting of predominantly small nucleotide deletions and a few characteristic structural variations. In ∼30% of the post-irradiated cells, complex genomic rearrangements, such as chromoplexy, chromothripsis, and breakage-fusion-bridge cycles, were resulted, indicating the stochastic and chaotic nature of DNA repair in the presence of the massive number of concurrent DNA double-strand breaks. These mutational signatures were confirmed in the genomes of 22 IR-induced secondary malignancies. With high-resolution genomic snapshots of irradiated cells, our findings provide deep insights into how IR-induced DNA damage and subsequent repair processes operate in mammalian cells.

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