TopBP1 interacts with BLM to maintain genome stability but is dispensable for preventing BLM degradation.
Schwab, Rebekka A
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Blackford, A., Nieminuszczy, J., Schwab, R. A., Galanty, Y., Jackson, S., & Niedzwiedz, W. (2015). TopBP1 interacts with BLM to maintain genome stability but is dispensable for preventing BLM degradation.. Mol Cell, 57 1133-1141. https://doi.org/10.1016/j.molcel.2015.02.012
The Bloom syndrome helicase BLM and topoisomerase-IIβ-binding protein 1 (TopBP1) are key regulators of genome stability. It was recently proposed that BLM phosphorylation on Ser338 mediates its interaction with TopBP1, to protect BLM from ubiquitylation and degradation (Wang et al., 2013). Here, we show that the BLM-TopBP1 interaction does not involve Ser338 but instead requires BLM phosphorylation on Ser304. Furthermore, we establish that disrupting this interaction does not markedly affect BLM stability. However, BLM-TopBP1 binding is important for maintaining genome integrity, because in its absence cells display increased sister chromatid exchanges, replication origin firing and chromosomal aberrations. Therefore, the BLM-TopBP1 interaction maintains genome stability not by controlling BLM protein levels, but via another as-yet undetermined mechanism. Finally, we identify critical residues that mediate interactions between TopBP1 and MDC1, and between BLM and TOP3A/RMI1/RMI2. Taken together, our findings provide molecular insights into a key tumor suppressor and genome stability network.
293FT cells, E1A antibody, and hr703 virus were gifts from Roger Grand, and DT40 cells and human LCLs were gifts from Julian Sale and Ian Hickson, respectively. We thank Nathan Ellis, Thanos Halazonetis, Frank Hänel, and Minoru Takata for plasmids; Grant Stewart and Yi Wang for antibodies; and Gabriel Balmus, Josep Forment, Abderrahmane Kaidi, Christine Schmidt, and Jon Travers for critical reading of the manuscript. This work was funded by a Worldwide Cancer Research International Fellowship and a WIMM/Medical Research Council Senior Non-Clinical Fellowship (MRCG0902418) to W.N., and by Polish Ministry of Science and Higher Education fellowship and Polish National Science Center grant number N303 571539 to J.N. The Jackson lab is funded by Cancer Research UK (CRUK) program grant C6/A11224, the European Research Council, and the European Community Seventh Framework Programme grant agreement number HEALTH-F2-2010-259893 (DDResponse). Core infrastructure funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, supplemented by CRUK.
Cancer Research Uk (None)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
External DOI: https://doi.org/10.1016/j.molcel.2015.02.012
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247950
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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