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Chromothripsis from DNA damage in micronuclei

Author

Listed:
  • Cheng-Zhong Zhang

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Alexander Spektor

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Hauke Cornils

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Joshua M. Francis

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and MIT)

  • Emily K. Jackson

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Shiwei Liu

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Matthew Meyerson

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and MIT
    Harvard Medical School
    Center for Cancer Genome Discovery, Dana-Farber Cancer Institute)

  • David Pellman

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and MIT
    Harvard Medical School
    Howard Hughes Medical Institute)

Abstract

Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome.

Suggested Citation

  • Cheng-Zhong Zhang & Alexander Spektor & Hauke Cornils & Joshua M. Francis & Emily K. Jackson & Shiwei Liu & Matthew Meyerson & David Pellman, 2015. "Chromothripsis from DNA damage in micronuclei," Nature, Nature, vol. 522(7555), pages 179-184, June.
  • Handle: RePEc:nat:nature:v:522:y:2015:i:7555:d:10.1038_nature14493
    DOI: 10.1038/nature14493
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    Cited by:

    1. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study," IJERPH, MDPI, vol. 19(18), pages 1-51, September.
    2. Lorenza Garribba & Giuseppina De Feudis & Valentino Martis & Martina Galli & Marie Dumont & Yonatan Eliezer & René Wardenaar & Marica Rosaria Ippolito & Divya Ramalingam Iyer & Andréa E. Tijhuis & Dia, 2023. "Short-term molecular consequences of chromosome mis-segregation for genome stability," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Qing Hu & Jose Espejo Valle-Inclán & Rashmi Dahiya & Alison Guyer & Alice Mazzagatti & Elizabeth G. Maurais & Justin L. Engel & Huiming Lu & Anthony J. Davis & Isidro Cortés-Ciriano & Peter Ly, 2024. "Non-homologous end joining shapes the genomic rearrangement landscape of chromothripsis from mitotic errors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Song Gao & Shuaibin Wang & Zhiying Zhao & Chao Zhang & Zhicao Liu & Ping Ye & Zhifang Xu & Baozhu Yi & Kai Jiao & Gurudatta A. Naik & Shi Wei & Soroush Rais-Bahrami & Sejong Bae & Wei-Hsiung Yang & Gu, 2022. "TUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3β/β-catenin signalling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study," IJERPH, MDPI, vol. 19(13), pages 1-27, June.
    7. Chunyang Bao & Richard W. Tourdot & Gregory J. Brunette & Chip Stewart & Lili Sun & Hideo Baba & Masayuki Watanabe & Agoston T. Agoston & Kunal Jajoo & Jon M. Davison & Katie S. Nason & Gad Getz & Ken, 2023. "Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    8. Jason Alexander Halliwell & Javier Martin-Gonzalez & Adnan Hashim & John Arne Dahl & Eva R. Hoffmann & Mads Lerdrup, 2024. "Sex-specific DNA-replication in the early mammalian embryo," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    9. Chen Sun & Kunal Kathuria & Sarah B. Emery & ByungJun Kim & Ian E. Burbulis & Joo Heon Shin & Daniel R. Weinberger & John V. Moran & Jeffrey M. Kidd & Ryan E. Mills & Michael J. McConnell, 2024. "Mapping recurrent mosaic copy number variation in human neurons," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. Stamatis Papathanasiou & Styliani Markoulaki & Logan J. Blaine & Mitchell L. Leibowitz & Cheng-Zhong Zhang & Rudolf Jaenisch & David Pellman, 2021. "Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    11. Xue-Ke Zhao & Pengwei Xing & Xin Song & Miao Zhao & Linxuan Zhao & Yonglong Dang & Ling-Ling Lei & Rui-Hua Xu & Wen-Li Han & Pan-Pan Wang & Miao-Miao Yang & Jing-Feng Hu & Kan Zhong & Fu-You Zhou & Xu, 2021. "Focal amplifications are associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    12. Mihoko Saito-Adachi & Natsuko Hama & Yasushi Totoki & Hiromi Nakamura & Yasuhito Arai & Fumie Hosoda & Hirofumi Rokutan & Shinichi Yachida & Mamoru Kato & Akihiko Fukagawa & Tatsuhiro Shibata, 2023. "Oncogenic structural aberration landscape in gastric cancer genomes," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    13. Kate M. MacDonald & Shirony Nicholson-Puthenveedu & Maha M. Tageldein & Sarika Khasnis & Cheryl H. Arrowsmith & Shane M. Harding, 2023. "Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    14. Jimyung Seo & HyunSeok Kim & Kyoung Il Min & Changgon Kim & Yongsoo Kwon & Zhenlong Zheng & Yusung Kim & Hyung-Soon Park & Young Seok Ju & Mi Ryung Roh & Kee Yang Chung & Joon Kim, 2022. "Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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