Highlights of This Issue

Abstract

Inhibition of DNA polymerase β (Polβ) enhances the cytotoxicity of chemotherapeutic DNA-damaging agents. To define the mechanism of cell death resulting from Polβ inhibition, Tang and colleagues depleted human cells of Polβ and demonstrate that unrepaired base excision repair (BER) intermediates elicit hyperactivation of poly(ADP) ribose synthesis causing cell death via depletion of NAD+ and other energy-related metabolites. This study implicates a linkage between BER, cell survival, and cellular bioenergetics after exposure to chemotherapeutic alkylating agents and has significant implications for therapeutic development of DNA repair and NAD+ biosynthesis inhibitors.The CXCR4 and CXCR7 receptors that bind prometastatic α-chemokine SDF- 1 were cloned and their activities were analyzed in a model of less metastatic human embryonal-rhabdomyosarcoma cell line (RD) and more metastatic alveolar-like rhabdomyosarcoma (RD cells transduced with PAX3-FKHR fusion gene). While the expression of CXCR4 required NRF-1 binding site and was additionally upregulated by direct interaction of NRF-1 with PAX3-FKHR, CXCR7 promoter activity required a proximal NF-κB binding motif. Moreover, while hypoxia enhanced expression of both receptors on RD cells, it inhibited CXCR7 expression in RD/PAX3-FKHR cells. Thus, the change in CXCR4/CXCR7 ratio by PAX3-FKHR or hypoxia modulates rhabdomyosarcoma metastasis.Thyroid hormone receptors (TR) play important roles in normal physiology and development, whereas dominant-negative TR mutants are associated with certain neoplasia, including human hepatocellular carcinoma (HCC). Chan and Privalsky report that the dominant-negative properties of two HCC-TR mutants map to lesions at lysine 74, an allosteric sensor that, in wild-type TRs, couples DNA binding to transcriptional regulation. These results reveal a mutational hot spot by which TRs can acquire dominant-negative activity, and help improve our understanding of how wild-type and mutant nuclear receptors recognize DNA so as to confer gene repression or activation.Because the activation of STAT3 mediates proliferation and metastasis of numerous human cancers, including multiple myleoma, inhibitors of this pathway are highly desirable. Sandur and colleagues report the identification of a compound plumbagin from an Ayurvedic plant Chitrak (Plumbago zeylanica) that can suppress the activation of STAT3 through the induction of expression of a protein tyrosine phosphatase that specifically dephosphorylates STAT3. Additionally, plumbagin inhibits the activation of upstream kinases c-Src, JAK1, and JAK2. This kind of promiscuous mechanism of action of plumbagin is highly desirable for its potential for treatment of cancer.