The Bloom’s syndrome protein, BLM, is a member of the conserved RecQ helicase family. Although cell lines lacking BLM exist, these exhibit progressive genomic instability that makes distinguishing primary from secondary effects of BLM loss problematic. In order to be able to acutely disable BLM function in cells, we undertook a high throughput screen of a chemical compound library for small molecule inhibitors of BLM. We present ML216, a potent inhibitor of the DNA unwinding activity of BLM. ML216 shows cell-based activity, and can induce sister chromatid exchanges, enhance to the toxicity of aphidicolin and exert anti-proliferative activity in cells expressing BLM, but not in those lacking BLM. These data indicate that ML216 shows strong selectively for BLM in cultured cells. We discuss the potential utility of such a BLM-targeting compound as an anticancer agent.
Background: RECQL4 is a RecQ helicase mutated in Rothmund-Thomson Syndrome (RTS) and has a functional role in DNA replication and repair. Results: RECQL4-depleted and RTS patient cells show telomere abnormalities and that RECQL4 interacts with telomeric DNA and related proteins. Conclusion: RECQL4 is involved in telomere maintenance. Significance: The RecQ helicase RECQL4 is involved in telomere replication and maintenance. This establishes a connection between telomere function and a disease with premature aging phenotype.
Background: NEIL2 (Nei-like 2) is a mammalian oxidized base-specific DNA glycosylase. Results: Neil2-null mice accumulate oxidative damage in transcribed genes and are susceptible to inflammatory agents.
Conclusion:In long-lived species, NEIL2 plays a critical role in maintaining genomic integrity and tissue homeostasis. Significance: We provide in vivo evidence for NEIL2's role in preferential repair of oxidized bases in active genes in mammals.
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