Genetic instability from a single S phase after whole-genome duplication.
Nature
; 604(7904): 146-151, 2022 04.
Article
em En
| MEDLINE
| ID: mdl-35355016
ABSTRACT
Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications-doublings of the entire complement of chromosomes-are linked to genetic instability and frequently found in human cancers1-3. It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis4-8; however, the immediate consequences of tetraploidy in the first interphase are not known. This is a key question because single whole-genome duplication events such as cytokinesis failure can promote tumorigenesis9. Here we find that human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Fase S
/
Duplicação Gênica
/
Instabilidade Cromossômica
/
Tetraploidia
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article