4.6 Article

Overexpression of TopBP1, a canonical ATR/Chk1 activator, paradoxically hinders ATR/Chk1 activation in cancer

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 296, Issue -, Pages -

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ELSEVIER
DOI: 10.1016/j.jbc.2021.100382

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Funding

  1. National Institutes of Health [R01CA100857]
  2. Rivkin Center for Ovarian Cancer Pilot Award [R01CA203824]
  3. Department of Defense [W81XWH-18-1-0329, W81XWH-19-1-0369]

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TopBP1 regulates the activation of ATR/Chk1 in a biphasic, concentration-dependent manner, with excessive accumulation hindering the checkpoint response and leading to genomic instability. Moderate depletion of TopBP1 enhances checkpoint response after replicative stress in cancer cells, suggesting TopBP1 overexpression as a new mechanism contributing to genomic instability during tumorigenesis.
Topoisomerase II beta-binding protein 1 (TopBP1) is involved in cellular replication among other functions and is known to activate ATR/Chk1 during replicative stress. TopBP1 is also expressed at high levels in many cancers. However, the impact of TopBP1 overexpression on ATR/Chk1 activation and cancer development has not been investigated. Here we demonstrate that the degree of ATR/Chk1 activation is regulated by TopBP1 in a biphasic, concentration-dependent manner in a non-transformed MCF10A cell line and several cancer cell lines, including H1299, MDA-MB468, and U2OS. At low levels, TopBP1 activates ATR/Chk1, but once TopBP1 protein accumulates above an optimal level, it paradoxically leads to lower activation of ATR/Chk1. This is due to the perturbation of ATR-TopBP1 interaction and ATR chromatin loading by excessive TopBP1. Overexpression of TopBP1 thus hinders the ATR/Chk1 checkpoint response, leading to the impairment of genome integrity as demonstrated by the cytokinesis-block micronucleus assay. In contrast, moderate depletion of TopBP1 by shRNA in TopBP1-overexpressing cancer cells enhanced ATR/Chk1 activation and S-phase checkpoint response after replicative stress. The clinical significance of these findings is supported by an association between TopBP1 overexpression and genome instability in many types of human cancer. Taken together, our study illustrates an unexpected relationship between the levels of TopBP1 and the final functional outcome and suggests TopBP1 overexpression as a new mechanism directly contributing to genomic instability during tumorigenesis.U

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