Human TopBP1 ensures genome integrity during normal S phase

Ja Eun Kim, Sarah A. McAvoy, David I Smith, Junjie Chen

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Cell cycle checkpoints are essential for maintaining genomic integrity. Human topoisomerase II ding protein 1 (TopBP1) shares sequence similarity with budding yeast Dpb11, fission yeast Rad4/Cut5, and Xenopus Cut5, all of which are required for DNA replication and cell cycle checkpoints. Indeed, we have shown that human TopBP1 participates in the activation of replication checkpoint and DNA damage checkpoints, following hydroxyurea treatment and ionizing radiation. In this study, we address the physiological function of TopBP1 in S phase by using small interfering RNA. In the absence of exogenous DNA damage, TopBP1 is recruited to replicating chromatin. However, TopBP1 does not appear to be essential for DNA replication. TopBP1-deficient cells have increased H2AX phosphorylation and ATM-Chk 2 activation, suggesting the accumulation of DNA double-strand breaks in the absence of TopBP1. This leads to formation of gaps and breaks at fragile sites, 4N accumulation, and aberrant cell division. We propose that the cellular function of TopBP1 is to monitor ongoing DNA replication. By ensuring proper DNA replication, TopBP1 plays a critical role in the maintenance of genomic stability during normal S phase as well as following genotoxic stress.

Original languageEnglish (US)
Pages (from-to)10907-10915
Number of pages9
JournalMolecular and Cellular Biology
Volume25
Issue number24
DOIs
StatePublished - Dec 2005

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DNA Replication
S Phase
Genome
DNA Damage
Cell Cycle Checkpoints
Type II DNA Topoisomerase
Saccharomycetales
Hydroxyurea
Double-Stranded DNA Breaks
Schizosaccharomyces
Genomic Instability
Xenopus
Ionizing Radiation
Cell Division
Small Interfering RNA
Chromatin
Maintenance
Phosphorylation
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Human TopBP1 ensures genome integrity during normal S phase. / Kim, Ja Eun; McAvoy, Sarah A.; Smith, David I; Chen, Junjie.

In: Molecular and Cellular Biology, Vol. 25, No. 24, 12.2005, p. 10907-10915.

Research output: Contribution to journalArticle

Kim, Ja Eun ; McAvoy, Sarah A. ; Smith, David I ; Chen, Junjie. / Human TopBP1 ensures genome integrity during normal S phase. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 24. pp. 10907-10915.
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