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Haoyang Cai - One of the best experts on this subject based on the ideXlab platform.
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ChromothripsisDB: A Curated Database for the Documentation, Visualization, and Mining of Chromothripsis Data.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Haoyang CaiAbstract:ChromothripsisDB ( http://cgma.scu.edu.cn/ChromothripsisDB ) is a manually curated database containing a unified description of published Chromothripsis cases and relevant genomic aberrations. Available data includes copy number alterations, chromosome structural variations, and gene annotations. The criteria used for detecting Chromothripsis in each study are also provided. At present, the molecular mechanisms involved in Chromothripsis phenomenon are not fully understood. Thus, further studies with large number of identified Chromothripsis samples are needed. The current release of ChromothripsisDB contains more than 400 patient samples, representing over 100 research articles. It represents an extraordinary resource for mining the existing knowledge of Chromothripsis.
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Chromothripsis Detection and Characterization Using the CTLPScanner Web Server.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Jian Yang, Bo Liu, Haoyang CaiAbstract:Accurate detection of Chromothripsis event is important to study the mechanisms underlying this phenomenon. CTLPScanner ( http://cgma.scu.edu.cn/CTLPScanner/ ) is a web-based tool for identification and annotation of Chromothripsis-like pattern (CTLP) in genomic array data. In this chapter, we illustrate the utility of CTLPScanner for screening chromosome pulverization regions and give interpretation of the results. The web interface offers a set of parameters and thresholds for customized screening. We also provide practical recommendations for effective Chromothripsis detection. In addition to the user data processing module, CTLPScanner contains more than 50,000 preprocessed oncogenomic arrays, which allow users to explore the presence of Chromothripsis signatures from public data resources.
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CTLPScanner: a web server for Chromothripsis-like pattern detection
Nucleic acids research, 2016Co-Authors: Jian Yang, Bo Liu, Jixiang Liu, Liang Ouyang, Yi Chen, Haoyang CaiAbstract:Chromothripsis is a recently observed phenomenon in cancer cells in which one or several chromosomes shatter into pieces with subsequent inaccurate reassembly and clonal propagation. This type of event generates a potentially vast number of mutations within a relatively short-time period, and has been considered as a new paradigm in cancer development. Despite recent advances, much work is still required to better understand the molecular mechanisms of this phenomenon, and thus an easy-to-use tool is in urgent need for automatically detecting and annotating Chromothripsis. Here we present CTLPScanner, a web server for detection of Chromothripsis-like pattern (CTLP) in genomic array data. The output interface presents intuitive graphical representations of detected chromosome pulverization region, as well as detailed results in table format. CTLPScanner also provides additional information for associated genes in Chromothripsis region to help identify the potential candidates involved in tumorigenesis. To assist in performing meta-data analysis, we integrated over 50 000 pre-processed genomic arrays from The Cancer Genome Atlas and Gene Expression Omnibus into CTLPScanner. The server allows users to explore the presence of Chromothripsis signatures from public data resources, without carrying out any local data processing. CTLPScanner is freely available at http://cgma.scu.edu.cn/CTLPScanner/.
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ChromothripsisDB: a curated database of Chromothripsis
Bioinformatics (Oxford England), 2015Co-Authors: Jian Yang, Gaofeng Deng, Haoyang CaiAbstract:UNLABELLED Chromothripsis is a single catastrophic event that can lead to massive genomic rearrangements confined to one or a few chromosomes. It provides an alternative paradigm in cancer development and changes the conventional view that cancer develops in a stepwise progression. The mechanisms underlying Chromothripsis and their specific impact on tumorigenesis are still poorly understood, and further examination of a large number of identified Chromothripsis samples is needed. Unfortunately, this data are difficult to access, as they are scattered across multiple publications, come in different formats and descriptions, or are hidden in figures and supplementary materials. To improve access to this data and promote meta-analysis, we developed ChromothripsisDB, a manually curated database containing a unified description of all published Chromothripsis cases and relevant genomic aberrations. Currently, 423 Chromothripsis samples representing 107 research articles are included in our database. ChromothripsisDB represents an extraordinary resource for mining the existing knowledge of Chromothripsis, and will facilitate the identification of mechanisms involved in this phenomenon. AVAILABILITY AND IMPLEMENTATION ChromothripsisDB is freely available at http://cgma.scu.edu.cn/ChromothripsisDB CONTACT: haoyang.cai@scu.edu.cn SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens
BMC genomics, 2014Co-Authors: Haoyang Cai, Nitin Kumar, Homayoun C. Bagheri, Christian Von Mering, Mark D. Robinson, Michael BaudisAbstract:Chromothripsis is a recently discovered phenomenon of genomic rearrangement, possibly arising during a single genome-shattering event. This could provide an alternative paradigm in cancer development, replacing the gradual accumulation of genomic changes with a “one-off” catastrophic event. However, the term has been used with varying operational definitions, with the minimal consensus being a large number of locally clustered copy number aberrations. The mechanisms underlying these Chromothripsis-like patterns (CTLP) and their specific impact on tumorigenesis are still poorly understood. Here, we identified CTLP in 918 cancer samples, from a dataset of more than 22,000 oncogenomic arrays covering 132 cancer types. Fragmentation hotspots were found to be located on chromosome 8, 11, 12 and 17. Among the various cancer types, soft-tissue tumors exhibited particularly high CTLP frequencies. Genomic context analysis revealed that CTLP rearrangements frequently occurred in genomes that additionally harbored multiple copy number aberrations (CNAs). An investigation into the affected chromosomal regions showed a large proportion of arm-level pulverization and telomere related events, which would be compatible to a number of underlying mechanisms. We also report evidence that these genomic events may be correlated with patient age, stage and survival rate. Through a large-scale analysis of oncogenomic array data sets, this study characterized features associated with genomic aberrations patterns, compatible to the spectrum of “Chromothripsis”-definitions as previously used. While quantifying clustered genomic copy number aberrations in cancer samples, our data indicates an underlying biological heterogeneity behind these Chromothripsis-like patterns, beyond a well defined “chromthripsis” phenomenon.
Audrey Rousseau - One of the best experts on this subject based on the ideXlab platform.
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Whole genome duplication is an early event leading to aneuploidy in IDH-wild type glioblastoma
Oncotarget, 2018Co-Authors: Blandine Boisselier, Anne Coutolleau, Emmanuel Garcion, Philippe Guardiola, Frederic Dugay, Marc-antoine Belaud-rotureau, Philippe Menei, Audrey RousseauAbstract:Glioblastoma, the most frequent and lethal form of glioma, displays chromosome instability and recurrent somatic copy number alterations (SCNA). Chromothripsis and whole genome duplication (WGD) have been recently identified in cancer. In the present study, we analyzed SCNA and determine the ploidy pattern in 123 IDH-wild-type glioblastomas, using SNP array data. WGD and Chromothripsis events were validated using, respectively, FISH and CTLPScanner. WGD was detected in 11.4% glioblastomas (14/123) and was associated with TP53 mutation (p = 0.0068). It was an early event occurring after the recurrent SCNA observed in diffuse high-grade gliomas. Glioblastomas with WGD were more aneuploid compared to glioblastomas without WGD (p < 0.0001). Chromothripsis occurred in 29.3% glioblastomas (36/123) and mostly affected chromosomes 7, 9 and 12, with amplification of oncogenes (EGFR, MDM2/CDK4), and homozygous deletion of tumor suppressor genes (CDKN2A). There was a significant association between Chromothripsis and gene rearrangement at a given locus. WGD is an early genetic event significantly associated to TP53 mutation and leading to chromosome instability and aneuploidy in IDH-wild-type glioblastoma. Chromothripsis recurrently targets oncogenes and tumor suppressor genes that are key players in gliomagenesis and tumor progression. The occurrence of Chromothripsis points to underlying gene rearrangements (including gene fusions), potential therapeutic targets in glioblastoma.
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Whole genome duplication is an early event leading to aneuploidy in IDH-wild type glioblastoma
Oncotarget, 2018Co-Authors: Blandine Boisselier, Anne Coutolleau, Emmanuel Garcion, Philippe Guardiola, Frederic Dugay, Marc-antoine Belaud-rotureau, Philippe Menei, Audrey RousseauAbstract:Glioblastoma, the most frequent and lethal form of glioma, displays chromosome instability and recurrent somatic copy number alterations (SCNA). Chromothripsis and whole genome duplication (WGD) have been recently identified in cancer. In the present study, we analyzed SCNA and determine the ploidy pattern in 123 IDH-wild-type glioblastomas, using SNP array data. WGD and Chromothripsis events were validated using, respectively, FISH and CTLPScanner. WGD was detected in 11.4% glioblastomas (14/123) and was associated with TP53 mutation (p = 0.0068). It was an early event occurring after the recurrent SCNA observed in diffuse high-grade gliomas. Glioblastomas with WGD were more aneuploid compared to glioblastomas without WGD (p < 0.0001). Chromothripsis occurred in 29.3% glioblastomas (36/123) and mostly affected chromosomes 7, 9 and 12, with amplification of oncogenes (EGFR, MDM2/CDK4), and homozygous deletion of tumor suppressor genes (CDKN2A). There was a significant association between Chromothripsis and gene rearrangement at a given locus. WGD is an early genetic event significantly associated to TP53 mutation and leading to chromosome instability and aneuploidy in IDH-wild-type glioblastoma. Chromothripsis recurrently targets oncogenes and tumor suppressor genes that are key players in gliomagenesis and tumor progression. The occurrence of Chromothripsis points to underlying gene rearrangements (including gene fusions), potential therapeutic targets in glioblastoma.
David Pellman - One of the best experts on this subject based on the ideXlab platform.
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Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing
Nature Genetics, 2021Co-Authors: Mitchell L Leibowitz, Cheng-zhong Zhang, Logan J Blaine, Lili Sun, Stamatis Papathanasiou, Phillip A. Doerfler, Yu Yao, Mitchell J. Weiss, David PellmanAbstract:Chromothripsis, a chromosomal shattering event, can be elicited by micronuclei and chromosome bridges formed by CRISPR–Cas9-generated double-stranded breaks. Extensive chromosomal rearrangements may thus be an on-target effect of genome editing. Genome editing has therapeutic potential for treating genetic diseases and cancer. However, the currently most practicable approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of chromosome structural abnormalities. Here, using model cells and single-cell whole-genome sequencing, as well as by editing at a clinically relevant locus in clinically relevant cells, we show that CRISPR–Cas9 editing generates structural defects of the nucleus, micronuclei and chromosome bridges, which initiate a mutational process called Chromothripsis. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer. These results demonstrate that Chromothripsis is a previously unappreciated on-target consequence of CRISPR–Cas9-generated DSBs. As genome editing is implemented in the clinic, the potential for extensive chromosomal rearrangements should be considered and monitored.
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Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing
2020Co-Authors: Mitchell L Leibowitz, Cheng-zhong Zhang, Logan J Blaine, Stamatis Papathanasiou, Phillip A. Doerfler, Yu Yao, Mitchell J. Weiss, David PellmanAbstract:Genome editing has promising therapeutic potential for genetic diseases and cancer (1, 2). However, the most practicable current approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of structural chromosomal abnormalities. Here, we show that a catastrophic mutational process called Chromothripsis is a previously unappreciated consequence of CRISPR-Cas9-mediated DSBs. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer (3-6). Using model cell systems and a genome editing protocol similar to ones in clinical trials (7) (NCT03655678, NCT03745287) we show that CRISPR-Cas9-mediated DNA breaks generate abnormal nuclear structures--micronuclei and chromosome bridges--that trigger Chromothripsis. Chromothripsis is an on-target toxicity that may be minimized by cell manipulation protocols or screening but cannot be completely avoided in many genome editing applications.
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nuclear envelope assembly defects link mitotic errors to Chromothripsis
Nature, 2018Co-Authors: Shiwei Liu, Mijung Kwon, Mark Mannino, Nachen Yang, Fioranna Renda, Alexey Khodjakov, David PellmanAbstract:Defects in the architecture or integrity of the nuclear envelope are associated with a variety of human diseases1. Micronuclei, one common nuclear aberration, are an origin for Chromothripsis2, a catastrophic mutational process that is commonly observed in cancer3–5. Chromothripsis occurs after micronuclei spontaneously lose nuclear envelope integrity, which generates chromosome fragmentation6. Disruption of the nuclear envelope exposes DNA to the cytoplasm and initiates innate immune proinflammatory signalling7. Despite its importance, the basis of the fragility of the micronucleus nuclear envelope is not known. Here we show that micronuclei undergo defective nuclear envelope assembly. Only ‘core’ nuclear envelope proteins8,9 assemble efficiently on lagging chromosomes, whereas ‘non-core’ nuclear envelope proteins8,9, including nuclear pore complexes (NPCs), do not. Consequently, micronuclei fail to properly import key proteins that are necessary for the integrity of the nuclear envelope and genome. We show that spindle microtubules block assembly of NPCs and other non-core nuclear envelope proteins on lagging chromosomes, causing an irreversible defect in nuclear envelope assembly. Accordingly, experimental manipulations that position missegregated chromosomes away from the spindle correct defective nuclear envelope assembly, prevent spontaneous nuclear envelope disruption, and suppress DNA damage in micronuclei. Thus, during mitotic exit in metazoan cells, chromosome segregation and nuclear envelope assembly are only loosely coordinated by the timing of mitotic spindle disassembly. The absence of precise checkpoint controls may explain why errors during mitotic exit are frequent and often trigger catastrophic genome rearrangements4,5. The mitotic spindle prevents normal nuclear envelope assembly on missegregated chromosomes, leading to spontaneous envelope disruption of micronuclei and subsequent genome instability.
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Comprehensive analysis of Chromothripsis in 2,658 human cancers using whole-genome sequencing
2018Co-Authors: Isidro Cortes-ciriano, June Koo Lee, Dhawal Jain, Youngsook L. Jung, Lixing Yang, Dmitry A. Gordenin, Leszek J Klimczak, Cheng-zhong Zhang, David PellmanAbstract:Chromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that Chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of Chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that Chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical Chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that Chromothripsis is a major process driving genome evolution in human cancer.
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Chromothripsis a new mechanism for rapid karyotype evolution
Annual Review of Genetics, 2015Co-Authors: Mitchell L Leibowitz, Cheng-zhong Zhang, David PellmanAbstract:Chromosomal rearrangements are generally thought to accumulate gradually over many generations. However, DNA sequencing of cancer and congenital disorders uncovered a new pattern in which multiple rearrangements arise all at once. The most striking example, Chromothripsis, is characterized by tens or hundreds of rearrangements confined to a single chromosome or to local regions over a few chromosomes. Genomic analysis of Chromothripsis and the search for its biological mechanism have led to new insights on how chromosome segregation errors can generate mutagenesis and changes to the karyotype. Here, we review the genomic features of Chromothripsis and summarize recent progress on understanding its mechanism. This includes reviewing new work indicating that one mechanism to generate Chromothripsis is through the physical isolation of chromosomes in abnormal nuclear structures (micronuclei). We also discuss connections revealed by recent genomic analysis of cancers between Chromothripsis, chromosome bridges...
Peter J. Campbell - One of the best experts on this subject based on the ideXlab platform.
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APOBEC3-dependent kataegis and TREX1-driven Chromothripsis during telomere crisis
Nature Genetics, 2020Co-Authors: John Maciejowski, Dmitry A. Gordenin, Leszek J Klimczak, Peter J. Campbell, Aikaterini Chatzipli, Alexandra Dananberg, Kevan Chu, Eleonore Toufektchan, Titia De LangeAbstract:Nucleic acid processing by the cytoplasmic exonuclease TREX1 and cytosine editing by APOBEC3B drive Chromothripsis and kataegis during telomere crisis. Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes^ 1 – 5 . Here we examine the mechanism underlying Chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes^ 4 , plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage–fusion–bridge cycles and simple genome rearrangements rather than Chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that Chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.
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APOBEC3-dependent kataegis and TREX1-driven Chromothripsis during telomere crisis.
Nature genetics, 2020Co-Authors: John Maciejowski, Dmitry A. Gordenin, Leszek J Klimczak, Peter J. Campbell, Aikaterini Chatzipli, Alexandra Dananberg, Kevan Chu, Eleonore Toufektchan, Titia De LangeAbstract:Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1-5. Here we examine the mechanism underlying Chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage-fusion-bridge cycles and simple genome rearrangements rather than Chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that Chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.
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apobec3b dependent kataegis and trex1 driven Chromothripsis in telomere crisis
bioRxiv, 2019Co-Authors: Aikaterini Chatzipli, John Maciejowski, Alexandra Dananberg, Titia De Lange, Peter J. CampbellAbstract:Chromothripsis and kataegis are frequently observed in cancer and can arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1–5. Here we report on the mechanism underlying Chromothripsis and kataegis using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In absence of TREX1, the genome alterations induced by telomere crisis primarily involve Breakage-Fusion-Bridge cycles and simple genome rearrangements rather than Chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. In addition, APOBEC3B increased the frequency of chromothriptic fragmentation, possibly due to strand breakage after cytosine deamination. These data reveal that Chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.
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4 Patterns of clustered mutational processes: Pan-Cancer analysis of Chromothripsis, chromoplexy and kataegis
ESMO Open, 2018Co-Authors: Jonas Demeulemeester, Jan O. Korbel, Maxime Tarabichi, Matthew W. Fittall, P. Van Loo, Peter J. CampbellAbstract:Introduction Some mutational processes can generate multiple mutations in a single event, leading to substantial reconfiguration of the genome. Three such processes have been described: (i) Chromothripsis, in which tens to hundreds of dsDNA breaks occur simultaneously, clustered on one or a few chromosomes, with near-random stitching together of fragments; (ii) chromoplexy, in which repair of co-occurring dsDNA breaks, typically on different chromosomes, results in shuffled chains of rearrangements; and (iii) kataegis, a focal hypermutation process leading to clustered nucleotide substitutions, biassed towards a single DNA strand. Material and methods We characterised the Pan-Cancer Analysis of Whole Genomes 2778 cancer genomes for Chromothripsis, chromoplexy and kataegis. We refined existing methods and developed novel algorithms for detecting these events, and time their occurrence during tumour evolution. Results and discussions Kataegis was observed in 45.3% of all cancers, particularly in lung squamous cell carcinoma and bladder cancer. The events mostly bore the footprint of APOBEC cytidine deaminases (86.9%). Unexpectedly, 5.3% involved clusters of T>N mutations, often in a TpT or CpT context in tumours of the gastrointestinal tract. In lymphoid tumours, we find hotspots of clustered mutations indicative of off-target activity of AID and Pol. Chromoplexy was observed in 454 samples, frequently involving disease-specific genes. Prostate cancer chains involved TMPRSS2 and ERG . Multiple complex chains were also seen in thyroid cancer, affecting thyroid cancer genes such as IGF2BP3, BRAF and THADA. We identified Chromothripsis in 238 samples, most often sarcoma and melanoma. The events manifested in rather different patterns and frequency across tumour types. In stomach cancers, the events were typically limited to a single chromosome, whereas they often involved multiple chromosomes in sarcoma and glioblastoma. Overall, kataegis occurs late during tumour evolution, contributing substantially to subclonal diversification. In contrast, Chromothripsis and chromoplexy tended to be clonal. We find early clonal Chromothripsis, leading to promoter hijacking by TERT, in a subset of chromophobe kidney cancers. Chromothripsis also occurs early in evolution of several melanomas, enabling rapid amplification of CCND1 with frequent co-involvement of other cancer genes. Conclusion Clustered mutational events are widespread across tumour types and can generate multiple drivers as well as enable rapid subclonal diversification.
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Criteria for inference of Chromothripsis in cancer genomes.
Cell, 2013Co-Authors: Jan O. Korbel, Peter J. CampbellAbstract:Chromothripsis scars the genome when localized chromosome shattering and repair occurs in a one-off catastrophe. Outcomes of this process are detectable as massive DNA rearrangements affecting one or a few chromosomes. Although recent findings suggest a crucial role of Chromothripsis in cancer development, the reproducible inference of this process remains challenging, requiring that cataclysmic one-off rearrangements be distinguished from localized lesions that occur progressively. We describe conceptual criteria for the inference of Chromothripsis, based on ruling out the alternative hypothesis that stepwise rearrangements occurred. Robust means of inference may facilitate in-depth studies on the impact of, and the mechanisms underlying, Chromothripsis.
Titia De Lange - One of the best experts on this subject based on the ideXlab platform.
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APOBEC3-dependent kataegis and TREX1-driven Chromothripsis during telomere crisis
Nature Genetics, 2020Co-Authors: John Maciejowski, Dmitry A. Gordenin, Leszek J Klimczak, Peter J. Campbell, Aikaterini Chatzipli, Alexandra Dananberg, Kevan Chu, Eleonore Toufektchan, Titia De LangeAbstract:Nucleic acid processing by the cytoplasmic exonuclease TREX1 and cytosine editing by APOBEC3B drive Chromothripsis and kataegis during telomere crisis. Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes^ 1 – 5 . Here we examine the mechanism underlying Chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes^ 4 , plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage–fusion–bridge cycles and simple genome rearrangements rather than Chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that Chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.
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APOBEC3-dependent kataegis and TREX1-driven Chromothripsis during telomere crisis.
Nature genetics, 2020Co-Authors: John Maciejowski, Dmitry A. Gordenin, Leszek J Klimczak, Peter J. Campbell, Aikaterini Chatzipli, Alexandra Dananberg, Kevan Chu, Eleonore Toufektchan, Titia De LangeAbstract:Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1-5. Here we examine the mechanism underlying Chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage-fusion-bridge cycles and simple genome rearrangements rather than Chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that Chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.
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apobec3b dependent kataegis and trex1 driven Chromothripsis in telomere crisis
bioRxiv, 2019Co-Authors: Aikaterini Chatzipli, John Maciejowski, Alexandra Dananberg, Titia De Lange, Peter J. CampbellAbstract:Chromothripsis and kataegis are frequently observed in cancer and can arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1–5. Here we report on the mechanism underlying Chromothripsis and kataegis using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In absence of TREX1, the genome alterations induced by telomere crisis primarily involve Breakage-Fusion-Bridge cycles and simple genome rearrangements rather than Chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. In addition, APOBEC3B increased the frequency of chromothriptic fragmentation, possibly due to strand breakage after cytosine deamination. These data reveal that Chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.