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Mitochondria are eukaryotic cellular organelles that are known to produce energy through a process called oxidative phosphorylation. Besides their primary function, mitochondria are involved in various cellular processes, including cell growth, differentiation, signaling, metabolism, and senescence. Age-related changes cause a decline in mitochondrial quality and integrity due to increased mitochondrial mutations and oxidative damage. Thus, aging can severely impact mitochondrial functions,...
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Related Experiment Video

Updated: Jan 6, 2026

Mitochondria
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TopBP1 activates the ATR-ATRIP complex.

Akiko Kumagai1, Joon Lee, Hae Yong Yoo

  • 1Division of Biology 216-76, California Institute of Technology, Pasadena, CA 91125, USA.

Cell
|March 15, 2006
PubMed
Summary

Topoisomerase Binding Protein 1 (TopBP1) activates the ATR kinase, a crucial enzyme for DNA damage and replication checkpoints. This discovery reveals a key mechanism controlling ATR activity in cell cycle regulation.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The precise mechanisms controlling the kinase activity of ATR (Ataxia Telangiectasia and Rad3-related) remain largely unknown.
  • ATR is a central regulator of DNA replication and damage checkpoint responses.
  • TopBP1 (Topoisomerase Binding Protein 1) is implicated in DNA replication initiation and checkpoint control.

Purpose of the Study:

  • To elucidate the mechanism by which ATR kinase activity is regulated.
  • To identify the role of TopBP1 in ATR activation and checkpoint signaling.

Main Methods:

  • Recombinant expression and purification of Xenopus and human ATR and TopBP1 proteins.
  • In vitro kinase assays to measure ATR activity in the presence of TopBP1.
  • Analysis of ATR activation using Xenopus egg extracts and human cell lines.
  • Site-directed mutagenesis to inactivate the putative ATR-activating domain of TopBP1.

Main Results:

  • Recombinant TopBP1 significantly enhances the kinase activity of both Xenopus and human ATR.
  • A specific conserved domain within TopBP1, separate from its BRCT repeats, is responsible for ATR activation.
  • The isolated ATR-activating domain of TopBP1 can ectopically activate ATR signaling in cellular extracts and intact cells.
  • A TopBP1 mutant with an inactivated ATR-activating domain impairs checkpoint regulation in Xenopus egg extracts.

Conclusions:

  • TopBP1 is a critical activator of ATR kinase activity.
  • The interaction between TopBP1 and ATR is essential for initiating ATR-dependent signaling pathways.
  • This finding provides a fundamental insight into the regulation of DNA damage and replication checkpoints.