PREP1 tumor suppressor protects the late-replicating DNA by controlling its replication timing and symmetry.
Sci Rep
; 8(1): 3198, 2018 02 16.
Article
em En
| MEDLINE
| ID: mdl-29453404
ABSTRACT
The synthesis of middle-to-late-replicating DNA can be affected independently of the rest of the genome by down-regulating the tumor suppressor PREP1 (PKNOX1). Indeed, DNA combing shows that PREP1 down-regulation affects DNA replication rate, increases the number of simultaneously firing origins and the asymmetry of DNA replication, leading to DNA damage. Genome-wide analysis of replication timing by Repli-seq shows that, upon PREP1 down-regulation, 25% of the genome is replicated earlier in the S-phase. The targeted DNA sequences correspond to Lamin-Associated Domains (LADs), and include late-replicating (LRRs) and temporal transition regions (TTRs). Notably, the distribution of PREP1 DNA binding sites and of its target genes indicates that DNA replication defects are independent of the overall PREP1 transcriptional activity. Finally, PREP1 down-regulation causes a substantial decrease in Lamin B1 levels. This suggests that DNA is released from the nuclear lamina earlier than in the control cells and is available for replication, thus explaining timing defects and DNA damage.This is the first evidence that the replication timing of a specific fraction of the human genome is affected by PREP1 tumor suppressor. This previously unknown function might significantly contribute to the genomic instability observed in human tumors.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Genes Supressores de Tumor
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Proteínas de Homeodomínio
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Instabilidade Genômica
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Período de Replicação do DNA
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article