CHROMOTHRIPSIS FROM DNA DAMAGE IN MICRONUCLEI

By Cheng-Zhong Zhang, A. Spektor, H. Cornils, J. Francis, E. Jackson, Shiwei Liu, M. Meyerson, D. Pellman. Nature, 2015

1,073 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5b1382ad6e687c0c6de261306b0934cdca201493

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In Cancer Research

1. Matthew Meyerson
2. Chad Nusbaum

In Genetics

1. Chip Stewart

In Molecular Biology

1. Chip Stewart
2. Matthew Meyerson
3. Rameen Beroukhim
4. Chad Nusbaum

Citations in the corpus

• SvABA: genome-wide detection of structural variants and indels by local assembly (2018, background): “Linked reads are also particularly useful for long-range haplotyping of detected variants (Zheng et al. 2016).”
• Patterns of somatic structural variation in human cancer genomes (2020, neutral): “Chromothripsis 3 , in which chromosome shattering and rearrangement occur in a single catastrophic event 9,21 , leads to a pattern of oscillating copy number changes and localised clustering of tens to hundreds of breakpoints 22 .”
• Chromothripsis and kataegis induced by telomere crisis (2015, neutral): “A proposed explanation of the localized nature of chromothripsis is the sequestration of a chromosome (fragment) in a micronucleus where it is shattered while the rest of the genome remains intact (Zhang et al., 2015).”