Identification of a small molecule inhibitor of BLM helicase

Sussex Drug Discovery Centre

BLM helicase is a member of the RecQ helicase family of ATP-dependent proteins that separate the two strands of duplex DNA, allowing DNA replication and repair processes to proceed. Mutations in this protein result in Bloom’s syndrome (BS), characterised by genomic instability, particularly an increased frequency of sister chromatid exchanges (SCEs), and a predisposition to cancer development, amongst other clinical features. Patients often develop leukaemia’s and lymphoma’s although most types of cancer have been observed in this group. BLM has also been demonstrated to be involved in a process known as Alternative Lengthening of the Telomeres (ALT). This is a homologous recombination-mediated mechanism by which new telomeric DNA is synthesised from an existing DNA template. The finer details of this pathway are unknown but it is known that depletion of BLM by siRNA in ALT+ cells results in telomere shortening.

Telomeres are ‘caps’ at the ends of the chromosomes…

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