Nucleic Acids Research, 2001, Vol. 29, No. 15 3172-3180
© 2001 Oxford University Press
Cleavage of the Bloom’s syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase III
Unidad de Investigación, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, 38320 Tenerife, Spain, 1Wellcome Trust/Cancer Research Campaign Institute of Cancer and Developmental Biology and Department of Zoology, Cambridge University, Tennis Court Road, Cambridge CB2 1QR, UK, 2Imperial Cancer Research Fund, Medical Oncology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK and 3Institute of Veterinary Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
In higher eukaryotes, the integration of signals triggered in response to certain types of stress can result in programmed cell death. Central to these events is the sequential activation of a cascade of proteinases known as caspases. The final activated effector caspases of this cascade digest a number of cellular proteins, in some cases increasing their enzymatic activity, in others destroying their function. Of the proteins shown to be targets for caspase-mediated proteolysis, a surprisingly large proportion are proteins involved in the signalling or repair of DNA damage. Here we investigate whether BLM, the product of the gene mutated in Bloom’s syndrome, a human autosomal disease characterised by cancer predisposition and sunlight sensitivity, is cleaved during apoptosis. BLM interacts with topoisomerase III
and has been proposed to play an important role in maintaining genomic integrity through its roles in DNA repair and replication. We show that BLM is cleaved during apoptosis by caspase-3 and reveal that the main cleavage site is located at the junction between the N-terminal and central helicase domains of BLM. Proteolytic cleavage by caspase-3 produces a 120 kDa fragment, which contains the intact helicase domain and three smaller fragments, the relative amounts of which depend on time of incubation with caspase-3. The 120 kDa fragment retains the helicase activity of the intact BLM protein. However, its interaction with topoisomerase III is severely impaired. Since the BLM–topoisomerase interaction is believed to be necessary for many of the replication and recombination functions of BLM, we suggest that caspase-3 cleavage of BLM could alter the localisation and/or function of BLM and that these changes may be important in the process of apoptosis.
* To whom correspondence should be addressed. Tel: +34 922 319338; Fax: +34 922 319412; Email: rfreire{at}hecit.es
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