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Genome instability

RB moonlights in mitosis

Nature Reviews Molecular Cell Biology volume 11, page 541 (2010)Cite this article

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Loss of the RB pathway affects mitosis, so van Harn et al. arrested mouse embryonic fibroblasts in which the three RB family members were ablated (TKO-MEFs) in G2 by serum starvation; this induced the cyclin-dependent kinase inhibitor p21, produced DNA double-strand breaks and activated the homologous recombination repair pathway. Inhibiting DNA damage response (DDR) kinases accelerated cell cycle re-entry and progression into mitosis after release from serum starvation and downregulated p21 expression. These data indicate that serum-starved RB-deficient cells accumulate DNA damage during progression through the preceding S phase and thereby activate DDR pathways. Moreover, metaphase spreads of TKO-MEFs showed defects in centromeric sister chromatid cohesion and increased chromatid breaks, suggesting that damage persists in mitosis. Consistent with this, TKO-MEFs that re-entered the cell cycle after serum re-addition had increased copy number alterations. Sister chromatid cohesion is initiated during S phase by the cohesin complex, and the authors speculate that the RB pathway may affect proper loading of the cohesin complex.

Manning et al. show that downregulation of RB1 expression in TERT-immortalized RPE1 cells (which are diploid epithelial cells) using RNA interference induces aneuploidy and chromosome missegregation. RB1 knockdown delayed mitotic progression, increasing the proportion of cells in prometaphase. They also observed further mitotic defects and suggested that this might originate from a defect in the structure of the centromere, which is regulated by the cohesin and condensin complexes. Chromatin association of RAD21 — a subunit of the cohesin complex — was reduced in mitotic cells lacking RB1, suggesting that its loss impairs the loading or maintenance of the cohesin complex at the centromere.

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ORIGINAL RESEARCH PAPERS

  1. van Harn, T. et al. Loss of RB proteins causes genomic instability in the absence of mitogenic signalling. Genes Dev. 24, 1377–1388 (2010)

    Article  CAS  Google Scholar 

  2. Manning, A. L. et al. Loss of pRB causes centromere dysfunction and chromsome instability. Genes Dev. 24, 1364–1376 (2010)

    Article  CAS  Google Scholar 

  3. Coschi, C. H. et al. Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor suppressive. Genes Dev. 24, 1351–1363 (2010)

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Gemma K. Alderton, Senior Editor Nature Reviews Cancer,

    Gemma K. Alderton

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  1. Gemma K. Alderton
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Alderton, G. RB moonlights in mitosis. Nat Rev Mol Cell Biol 11, 541 (2010). https://doi.org/10.1038/nrm2951

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  • DOI: https://doi.org/10.1038/nrm2951

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