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Constitutive DNA damage is linked to DNA replication abnormalities in Bloom's syndrome cells

Oncogene volume 22, pages 8749–8757 (2003)Cite this article

Abstract

Bloom's syndrome (BS) is an autosomal recessive disorder associated with an elevated incidence of cancers. The gene mutated in BS, BLM, encodes a RecQ helicase family member. BS cells exhibit genomic instability, including excessive homologous recombination and chromosomal aberrations. We reported previously that BS cells also demonstrate increased error-prone nonhomologous endjoining, which could contribute to genomic instability in these cells. Here, we show that BS cells display an abnormality in the timing of replication of both early-replicating genes and late-replicating loci such as chromosomal fragile sites. This delayed replication is associated with a constitutively increased frequency of sites of DNA damage and repair, as determined by the presence of DNA repair factors such as RAD51 and Ku86. In addition, another RecQ family helicase, WRN, also localizes to these repair sites. The presence of these repair sites correlates with the temporal appearance of cyclin B1 expression, indicative of the cells having progressed beyond mid-S phase in the cell division cycle. Critically, these defects in BS cells are the direct result of loss of BLM function, because BS cells phenotypically ‘reverted’ following transfection with the BLM cDNA no longer show such defects. Thus, our data indicate that constitutive DNA damage is coupled to delayed DNA replication in BS cells.

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Acknowledgements

FVR is supported by the elimination of leukaemia fund (ELF). PSN and IDH are supported by Cancer Research UK. We thank Professor Stephen Baylin, Dr Chris Norbury and Dr Nicola Brady for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Haematological Medicine, Leukaemia Sciences Laboratories, The Rayne Institute, Guy's, King's and Thomas’ School of Medicine, 123 Coldharbour Lane, London, SE5 9NU, UK

    Feyruz V Rassool & Ghulam J Mufti

  2. Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK

    Philip S North & Ian D Hickson

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  1. Feyruz V Rassool
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Correspondence to Feyruz V Rassool.

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Rassool, F., North, P., Mufti, G. et al. Constitutive DNA damage is linked to DNA replication abnormalities in Bloom's syndrome cells. Oncogene 22, 8749–8757 (2003). https://doi.org/10.1038/sj.onc.1206970

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