DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis

Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis.

Download Full-text

Detecting presence of mutational signatures in cancer with confidence

10.1101/132597 ◽

2017 ◽

Cited By ~ 1

Author(s):

Xiaoqing Huang ◽

Damian Wojtowicz ◽

Teresa M. Przytycka

Keyword(s):

Breast Cancer ◽

Somatic Mutations ◽

Decomposition Methods ◽

R Package ◽

The Novel ◽

Cancer Etiology ◽

Mutational Signatures ◽

Dna Damage And Repair ◽

Cancer Genomes ◽

Additional Support

AbstractCancers arise as the result of somatically acquired changes in the DNA of cancer cells. However, in addition to the mutations that confer a growth advantage, cancer genomes accumulate a large number of somatic mutations resulting from normal DNA damage and repair processes as well as mutations triggered by carcinogenic exposures or cancer related aberrations of DNA mainte-nance machinery. These mutagenic processes often produce characteristic mutational patterns called mutational signatures. Decomposition of cancer’s mutation catalog into mutations consistent with such signatures can provide valuable information about cancer etiology. However, the results from diﬀerent decomposition methods are not always consistent. Hence, one needs to not only be able to decompose a patient’s mutational profile into signatures but also to establish the accuracy of such decomposition. We proposed two complementary ways of measuring confidence and stability of decomposition results and applied them to analyze mutational signatures in breast cancer genomes. We identified very stable and highly unstable signatures, as well as signatures that have been missed altogether. We also provided additional support for the novel signatures. Our results emphasize the importance of assessing the confidence and stability of inferred signature contributions. All tools developed in this paper have been implemented in an R package, called SignatureEstimation, which is available from https://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/index.cgi#signatureestimation.

Download Full-text

Structural Insight into the Mechanism of PALB2 Interaction with MRG15

Genes ◽

10.3390/genes12122002 ◽

2021 ◽

Vol 12 (12) ◽

pp. 2002

Author(s):

Jennifer Redington ◽

Jaigeeth Deveryshetty ◽

Lakshmi Kanikkannan ◽

Ian Miller ◽

Sergey Korolev

Keyword(s):

Breast Cancer ◽

Protein Interactions ◽

Genome Stability ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Chromosome 15 ◽

Dna Breaks ◽

Extended Surface ◽

Transcription Complexes ◽

Insight Into

The tumor suppressor protein partner and localizer of BRCA2 (PALB2) orchestrates the interactions between breast cancer susceptibility proteins 1 and 2 (BRCA1, -2) that are critical for genome stability, homologous recombination (HR) and DNA repair. PALB2 mutations predispose patients to a spectrum of cancers, including breast and ovarian cancers. PALB2 localizes HR machinery to chromatin and links it with transcription through multiple DNA and protein interactions. This includes its interaction with MRG15 (Morf-related gene on chromosome 15), which is part of many transcription complexes, including the HAT-associated and the HDAC-associated complexes. This interaction is critical for PALB2 localization in actively transcribed genes, where transcription/replication conflicts lead to frequent replication stress and DNA breaks. We solved the crystal structure of the MRG15 MRG domain bound to the PALB2 peptide and investigated the effect of several PALB2 mutations, including patient-derived variants. PALB2 interacts with an extended surface of the MRG that is known to interact with other proteins. This, together with a nanomolar affinity, suggests that the binding of MRG15 partners, including PALB2, to this region is mutually exclusive. Breast cancer-related mutations of PALB2 cause only minor attenuation of the binding affinity. New data reveal the mechanism of PALB2-MRG15 binding, advancing our understanding of PALB2 function in chromosome maintenance and tumorigenesis.

Download Full-text

The APOBEC3A deaminase drives episodic mutagenesis in cancer cells

10.1101/2021.02.14.431145 ◽

2021 ◽

Author(s):

Mia Petljak ◽

Kevan Chu ◽

Alexandra Dananberg ◽

Erik N. Bergstrom ◽

Patrick von Morgen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Human Cancer ◽

B Cell Lymphoma ◽

Lymphoma Cell ◽

Mutational Signatures ◽

Cytidine Deaminases ◽

Human Cancer Cells ◽

Cancer Genomes

ABSTRACTThe APOBEC3 family of cytidine deaminases is widely speculated to be a major source of somatic mutations in cancer1–3. However, causal links between APOBEC3 enzymes and mutations in human cancer cells have not been established. The identity of the APOBEC3 paralog(s) that may act as prime drivers of mutagenesis and the mechanisms underlying different APOBEC3-associated mutational signatures are unknown. To directly investigate the roles of APOBEC3 enzymes in cancer mutagenesis, candidate APOBEC3 genes were deleted from cancer cell lines recently found to naturally generate APOBEC3-associated mutations in episodic bursts4. Deletion of the APOBEC3A paralog severely diminished the acquisition of mutations of speculative APOBEC3 origins in breast cancer and lymphoma cell lines. APOBEC3 mutational burdens were undiminished in APOBEC3B knockout cell lines. APOBEC3A deletion reduced the appearance of the clustered mutation types kataegis and omikli, which are frequently found in cancer genomes. The uracil glycosylase UNG and the translesion polymerase REV1 were found to play critical roles in the generation of mutations induced by APOBEC3A. These data represent the first evidence for a long-postulated hypothesis that APOBEC3 deaminases generate prevalent clustered and non-clustered mutational signatures in human cancer cells, identify APOBEC3A as a driver of episodic mutational bursts, and dissect the roles of the relevant enzymes in generating the associated mutations in breast cancer and B cell lymphoma cell lines.

Download Full-text

The APOBEC3A deaminase drives episodic mutagenesis in cancer cells

10.21203/rs.3.rs-240585/v1 ◽

2021 ◽

Author(s):

John Maciejowski ◽

Mia Petljak ◽

Kevan Chu ◽

Alexandra Dananberg ◽

Erik Bergstrom ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Human Cancer ◽

B Cell Lymphoma ◽

Lymphoma Cell ◽

Mutational Signatures ◽

Cytidine Deaminases ◽

Human Cancer Cells ◽

Cancer Genomes

Abstract The APOBEC3 family of cytidine deaminases is widely speculated to be a major source of somatic mutations in cancer1–3. However, causal links between APOBEC3 enzymes and mutations in human cancer cells have not been established. The identity of the APOBEC3 paralog(s) that may act as prime drivers of mutagenesis and the mechanisms underlying different APOBEC3-associated mutational signatures are unknown. To directly investigate the roles of APOBEC3 enzymes in cancer mutagenesis, candidate APOBEC3 genes were deleted from cancer cell lines recently found to naturally generate APOBEC3-associated mutations in episodic bursts4. Deletion of the APOBEC3A paralog severely diminished the acquisition of mutations of speculative APOBEC3 origins in breast cancer and lymphoma cell lines. APOBEC3 mutational burdens were undiminished in APOBEC3B knockout cell lines. APOBEC3A deletion reduced the appearance of the clustered mutation types kataegis and omikli, which are frequently found in cancer genomes. The uracil glycosylase UNG and the translesion polymerase REV1 were found to play critical roles in the generation of mutations induced by APOBEC3A. These data represent the first evidence for a long-postulated hypothesis that APOBEC3 deaminases generate prevalent clustered and non-clustered mutational signatures in human cancer cells, identify APOBEC3A as a driver of episodic mutational bursts, and dissect the roles of the relevant enzymes in generating the associated mutations in breast cancer and B cell lymphoma cell lines.

Download Full-text

Mutational signatures associated with exposure to carcinogenic microplastic compounds bisphenol A and styrene oxide

NAR Cancer ◽

10.1093/narcan/zcab004 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Xiaoju Hu ◽

Antara Biswas ◽

Anchal Sharma ◽

Halle Sarkodie ◽

Ivy Tran ◽

...

Keyword(s):

Public Health ◽

Bisphenol A ◽

Styrene Oxide ◽

Systematic Evaluation ◽

Cancer Type ◽

Mutational Signatures ◽

Cellular Processes ◽

Genome Wide ◽

Cancer Genomes ◽

Environmental Agents

Abstract Microplastic pollutants in oceans and food chains are concerning to public health. Common plasticizing compounds Bisphenol-A (BPA) and Styrene-7,8-Oxide (SO) are now labeled as carcinogens. We show that BPA and SO cause deoxyribonucleic acid damage and mutagenesis in human cells, and analyze the genome-wide point mutation and genomic rearrangement patterns associated with BPA and SO exposure. A subset of the single- and doublet base substitutions shows mutagenesis near or at guanine, consistent with these compounds’ preferences to form guanosine adducts. Presence of other mutational signatures suggest additional mutagenesis probably due to complex effects of BPA and SO on diverse cellular processes. Analyzing data for 19 cancer cohorts, we find that tumors of digestive and urinary organs show relatively high similarity in mutational profiles, and the burden of such mutations increases with age. Even within the same cancer type, proportions of corresponding mutational patterns vary among the cohorts from different countries, as does the amount of microplastic waste in ocean waters. BPA and SO are relatively mild mutagens, and other environmental agents can also potentially generate similar, complex mutational patterns in cancer genomes. Nonetheless, our findings call for systematic evaluation of public health consequences of microplastic exposure worldwide.

Download Full-text

Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer

10.1101/568568 ◽

2019 ◽

Author(s):

Yoo-Ah Kim ◽

Damian Wojtowicz ◽

Rebecca Sarto Basso ◽

Itay Sason ◽

Welles Robinson ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Somatic Mutations ◽

Cancer Genome ◽

Mutational Signatures ◽

Dna Damage And Repair ◽

Cancer Genomes ◽

Cancer Mutations ◽

Functional Pathways ◽

Dna Maintenance

AbstractStudies of cancer mutations typically focus on identifying cancer driving mutations. However, in addition to the mutations that confer a growth advantage, cancer genomes accumulate a large number of passenger somatic mutations resulting from normal DNA damage and repair processes as well as mutations triggered by carcinogenic exposures or cancer related aberrations of DNA maintenance machinery. These mutagenic processes often produce characteristic mutational patterns called mutational signatures. Understanding the etiology of the mutational signatures shaping a cancer genome is an important step towards understanding tumorigenesis. Considering mutational signatures as phenotypes, we asked two complementary questions (i) what are functional pathways whose geneexpressionprofiles are associated with mutational signatures, and (ii) what aremutated pathways(if any) that might underlie specific mutational signatures? We have been able to identify pathways associated with mutational signatures on both expression and mutation levels. In particular, our analysis provides novel insights into mutagenic processes in breast cancer by capturing important differences in the etiology of different APOBEC related signatures and the two clock-like signatures. These results are important for understanding mutagenic processes in cancer and for developing personalized drug therapies.

Download Full-text