Mechanisms generating cancer genome complexity from a single cell division error.
Science
; 368(6488)2020 04 17.
Article
em En
| MEDLINE
| ID: mdl-32299917
ABSTRACT
The chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes alongside chromothripsis, another catastrophic mutational phenomenon. We explain this association by elucidating a mutational cascade that is triggered by a single cell division error-chromosome bridge formation-that rapidly increases genomic complexity. We show that actomyosin forces are required for initial bridge breakage. Chromothripsis accumulates, beginning with aberrant interphase replication of bridge DNA. A subsequent burst of DNA replication in the next mitosis generates extensive DNA damage. During this second cell division, broken bridge chromosomes frequently missegregate and form micronuclei, promoting additional chromothripsis. We propose that iterations of this mutational cascade generate the continuing evolution and subclonal heterogeneity characteristic of many human cancers.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Quebra Cromossômica
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Carcinogênese
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Mitose
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Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2020
Tipo de documento:
Article