53
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      A new development in DNA repair modulation : Discovery of a BLM helicase inhibitor

      article-commentary

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Bloom’s syndrome (BS) is a rare autosomal recessive genetic disorder characterized by predisposition to a wide variety of cancers observed in the normal population. 1 The BLM gene defective in BS encodes a RecQ DNA helicase (BLM) that is important for genomic stability by suppressing sister chromatid exchanges (SCE) that arise during homologous recombination (HR). 2 In fact, SCE frequency of patient cells is used for clinical diagnosis of BS. BLM helicase is believed to suppress SCEs by channeling DNA molecules away from pathways leading to crossover products through its DNA unwinding function and interaction with protein partners (e.g., human Topoisomerase IIIα). 3 Targeting DNA helicases for therapeutic purposes has attracted interest with the discovery of other DNA repair inhibitors, highlighted by poly(ADP)ribosylase (PARP) inhibitors used in synthetic lethal approaches to attenuate carcinogenesis in HR-defective BRCA1/2-deficient tumors. 4 Small molecules (< 800 Daltons) can penetrate cell membranes and represent a potentially suitable class of compounds for therapeutic use, such as anti-cancer drugs. In the January 24, 2013 issue of Chemistry and Biology, Nguyen et al. reported their discovery of a small molecule inhibitor of BLM helicase. 5 From a high throughput screen of a chemical compound library and medicinal chemistry optimization, a small molecule (ML216) was identified that inhibited BLM helicase activity on a forked duplex DNA substrate in vitro (IC50 ~3 μM) by preventing BLM binding to DNA. 5 Cultured human fibroblasts exposed to ML216 (50 μM) displayed reduced proliferation, a statistically significant increase in SCE frequency, and elevated sensitivity to aphidicolin, an inhibitor of replicative DNA polymerases. The specificity for ML216 targeting BLM in cell-based experiments was suggested because BLM-deficient cells were resistant to the phenotypic effects of ML216. The BLM helicase inhibitor discovery may provide a new strategy for understanding molecular functions of BLM required for its role in chromosomal stability, and also potential development of a new class of chemotherapy drugs to treat tumors which rely heavily on BLM for proliferation. From a biochemist’s perspective, it is intriguing that ML216 potently inhibited BLM unwinding of a forked DNA duplex substrate, but only modestly affected unwinding of other DNA substrates (G-quadruplex, Holliday Junction, or plasmid-based D-loop) at much higher concentrations of drug. 5 The specificity of ML216 (and conceivably other helicase inhibitors) may allow an experimental approach to dissect molecular requirements of the helicase for its role(s) in genome stability. Although ML216 inhibited unwinding by the sequence-related BLM and WRN helicases similarly in vitro, the apparent dependence on BLM for ML216 to exert its biological effects in human cells suggests BLM specificity for the drug’s mechanism of action in vivo. A co-crystal structure of BLM in complex with inhibitor would be informative. Cellular cues in vivo may induce a specific conformation of WRN that makes it resistant to ML216. Direct or water-mediated contacts of the small molecule with poorly conserved amino acid residues of BLM that are distal in the primary structure but proximal in the tertiary structure may be critical for drug action. Other studies reporting pharmacological inhibition of DNA repair protein function have also shown a dependence on target protein for the small molecule’s cellular effect. An inhibitor of WRN helicase (NSC 19630) was discovered that inhibited proliferation and induced DNA damage and apoptosis in human cancer cells in a WRN-dependent manner. 6 Although the mechanism of action whereby NSC 19630 interferes with critical function(s) of WRN at the cellular level is unknown, there are several avenues to investigate. The WRN-inhibitor drug complex may prevent WRN from interacting favorably with its protein partners or cause formation of a static protein-DNA complex that is deleterious to normal biological DNA transactions. Since NSC 19630 exerted only a marginal effect on DNA-dependent WRN ATPase or exonuclease activity in vitro at very high drug concentrations, 6 WRN inhibitor is likely to operate by a mechanism distinct from that of the BLM inhibitor which adversely affected BLM DNA binding and DNA-dependent ATPase activity at relatively low drug concentrations. 5 Our current hypothesis is that the biological effects of NSC 19630 may at least partly reflect an inactive WRN helicase-drug complex trapped on DNA repair or replication intermediates. Further studies will be necessary to determine if this is the case. However, a recent study of clinical PARP inhibitors that operate in a PARP-dependent manner hinted at a provocative scenario. Small molecule inhibition of PARP1 or PARP2 became more cytotoxic than genetic depletion of PARP by causing PARP to become trapped on DNA at damaged sites. 7 This finding suggests a reasonable mechanism for a class of DNA helicase inhibitors (like NSC 19630), but more research is necessary. Understanding the mechanisms of DNA repair inhibitors has potential clinical significance. Chemo- and radio-therapy approaches to combat cancer are largely based on introducing DNA damage leading to double strand breaks (DSB). Recently, a small molecule inhibitor (SCR7) of DNA Ligase IV responsible for nonhomologous end-joining (NHEJ) was discovered and found to inhibit NHEJ in a Ligase IV-dependent manner, 8 reminiscent of the helicase and PARP inhibitors discussed above. Importantly, SCR7 impeded tumor progression in mouse models. 8 Hopefully, further research and clinical applications for helicase inhibitors will prove to be promising.

          Related collections

          Most cited references4

          • Record: found
          • Abstract: found
          • Article: not found

          The Bloom's syndrome gene product is homologous to RecQ helicases.

          The Bloom's syndrome (BS) gene, BLM, plays an important role in the maintenance of genomic stability in somatic cells. A candidate for BLM was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping. In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. The presence of chain-terminating mutations in the candidate gene in persons with BS proved that it was BLM.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression.

            DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens. Copyright © 2012 Elsevier Inc. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Homologous recombination in cancer development, treatment and development of drug resistance.

              Although DNA double-strand breaks (DSBs) are substrates for homologous recombination (HR) repair, it is becoming apparent that DNA lesions produced at replication forks, for instance by many anticancer drugs, are more significant substrates for HR repair. Cells defective in HR are hypersensitive to a wide variety of anticancer drugs, including those that do not produce DSBs. Several cancers have mutations in or epigenetically silenced HR genes, which explain the genetic instability that drives cancer development. There are an increasing number of reports suggesting that mutation or epigenetic silencing of HR genes explains the sensitivity of cancers to current chemotherapy treatments. Furthermore, there are also many examples of re-expression of HR genes in tumours to explain drug resistance. Emerging data suggest that there are several different subpathways of HR, which can compensate for each other. Unravelling the overlapping pathways in HR showed that BRCA1- and BRCA2-defective cells rely on the PARP protein for survival. This synthetic lethal interaction is now being exploited for selective treatment of BRCA1- and BRCA2-defective cancers with PARP inhibitors. Here, I discuss the diversity of HR and how it impacts on cancer with a particular focus on how HR can be exploited in future anticancer strategies.
                Bookmark

                Author and article information

                Journal
                Cell Cycle
                Cell Cycle
                CC
                Cell Cycle
                Landes Bioscience
                1538-4101
                1551-4005
                01 March 2013
                01 March 2013
                : 12
                : 5
                : 713-714
                Affiliations
                [1 ]Laboratory of Molecular Gerontology; National Institute on Aging; National Institutes of Health (NIH); Biomedical Research Center; Baltimore, MD USA
                [2 ]Department of Oncology; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Georgetown University; Washington, DC USA
                Author notes
                [* ]Correspondence to: Robert M. Brosh, Jr., Email: BroshR@ 123456mail.nih.gov
                Article
                2013CC12-5-Banerjee 23953
                10.4161/cc.23953
                3610714
                23422862
                fdadad46-ec02-4441-bc9b-f761595d8894
                Copyright © 2013 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                Categories
                Editorials: Cell Cycle Features

                Cell biology
                anticancer therapy,bloom's syndrome,dna repair,helicase,high-throughput screening,inhibitor,molecular probes,recq,small molecules,synthetic lethality

                Comments

                Comment on this article