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Jiewen Zhu,
Longen Zhou,
Guikai Wu,
Heiko Konig,
Xiaoqin Lin,
Guideng Li,
Xiao-Long Qiu,
Chi-Fen Chen,
Chun-Mei Hu,
Erin Goldblatt,
Ravi Bhatia,
A Richard Chamberlin,
Phang-Lang Chen, Wen-Hwa Lee
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ABSTRACT: RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome-mediated RAD51 protein degradation, reduces ionizing radiation-induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib-resistant CML model bearing the T315I Bcr-abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34(+) progenitor cells from CML patients resistant to known BCR-ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad-spectrum therapeutics for difficult-to-treat cancers.
EMBO Molecular Medicine 01/2013; · 10.33 Impact Factor
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ABSTRACT: We reported that non-targeting siRNA (NT-siRNA) stress induces non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) expression to cooperate with exoribonuclease XRN2 for releasing the stress [Wei,P.C., Lo,W.T., Su,M.I., Shew,J.Y. and Lee,W.H. (2011) Non-targeting siRNA induces NPGPx expression to cooperate with exoribonuclease XRN2 for releasing the stress. Nucleic Acids Res., 40, 323-332]. However, how NT-siRNA stress inducing NPGPx expression remains elusive. In this communication, we showed that the proximal promoter of NPGPx contained a mixed G-quadruplex (G4) structure, and disrupting the structure diminished NT-siRNA induced NPGPx promoter activity. We also demonstrated that nucleolin (NCL) specifically bonded to the G4-containing sequences to replace the originally bound Sp1 at the NPGPx promoter on NT-siRNA stress. Consistently, overexpression of NCL further increased NPGPx promoter activity, whereas depletion of NCL desensitized NPGPx promoter to NT-siRNA stress. These results suggest that the cis-element with mixed G4 structure at the NPGPx promoter plays an essential role for its transactivation mediated by NCL to release cells from NT-siRNA stress.
Nucleic Acids Research 12/2012; · 8.03 Impact Factor
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Pei-Chi Wei,
Yi-Hsuan Hsieh,
Mei-I Su,
X-J Jiang,
Pang-Hung Hsu,
Wen-Ting Lo,
Jui-Yun Weng,
Yung-Ming Jeng,
Ju-Ming Wang,
Phang-Lang Chen,
Yi-Cheng Chang,
Kuo-Fen Lee,
Ming-Daw Tsai,
Jin-Yuh Shew, Wen-Hwa Lee
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ABSTRACT: NPGPx is a member of the glutathione peroxidase (GPx) family; however, it lacks GPx enzymatic activity due to the absence of a critical selenocysteine residue, rendering its function an enigma. Here, we show that NPGPx is a newly identified stress sensor that transmits oxidative stress signals by forming the disulfide bond between its Cys57 and Cys86 residues. This oxidized form of NPGPx binds to glucose-regulated protein (GRP)78 and forms covalent bonding intermediates between Cys86 of NPGPx and Cys41/Cys420 of GRP78. Subsequently, the formation of the disulfide bond between Cys41 and Cys420 of GRP78 enhances its chaperone activity. NPGPx-deficient cells display increased reactive oxygen species, accumulated misfolded proteins, and impaired GRP78 chaperone activity. Complete loss of NPGPx in animals causes systemic oxidative stress, increases carcinogenesis, and shortens life span. These results suggest that NPGPx is essential for releasing excessive ER stress by enhancing GRP78 chaperone activity to maintain physiological homeostasis.
Molecular cell 10/2012; · 14.61 Impact Factor
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ABSTRACT: Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-catenin into nucleus, leading to downregulation of c-myc and cyclin D1 via the phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in patients with breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and show that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes. Cancer Res; 72(18); 4652-61. ©2012 AACR.
Cancer Research 07/2012; 72(18):4652-61. · 7.86 Impact Factor
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ABSTRACT: Microenvironment plays an important role in cancer development. We have reported that the cancer-associated stromal cells exhibit phenotypic and functional changes compared to stromal cells neighboring to normal tissues. However, the molecular mechanisms as well as the maintenance of these changes remain elusive. Here we showed that through co-culture with breast cancer cells for at least three to four passages, breast normal tissue-associated fibroblasts (NAFs) gained persistent activity for promoting cancer cell invasion, partly via up-regulating ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1). Furthermore, we demonstrated that the DNA methylation pattern in the ADAMTS1 promoter has no alteration. Instead, the loss of EZH2 binding to the ADAMTS1 promoter and the resulting decrease of promoter-associated histone H3K27 methylation may account for the up-regulation of ADAMTS1. Importantly, the lack of EZH2 binding and the H3K27 methylation on the ADAMTS1 promoter were sustained in cancer cell-precocultured NAFs after removal of cancer cells. These results suggest that cancer cells are capable of inducing stromal fibroblasts to secrete ADAMTS1 persistently for their invasion and the effect is epigenetically inheritable.
PLoS ONE 01/2012; 7(4):e35128. · 4.09 Impact Factor
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ABSTRACT: Yeast SUV3 is a nuclear encoded mitochondrial RNA helicase that complexes with an exoribonuclease, DSS1, to function as an
RNA degradosome. Inactivation of SUV3 leads to mitochondrial dysfunctions, such as respiratory deficiency; accumulation of
aberrant RNA species, including excised group I introns; and loss of mitochondrial DNA (mtDNA). Although intron toxicity has
long been speculated to be the major reason for the observed phenotypes, direct evidence to support or refute this theory
is lacking. Moreover, it remains unknown whether SUV3 plays a direct role in mtDNA maintenance independently of its degradosome
activity. In this paper, we address these questions by employing an inducible knockdown system in Saccharomyces cerevisiae with either normal or intronless mtDNA background. Expressing mutants defective in ATPase (K245A) or RNA binding activities
(V272L or ΔCC, which carries an 8-amino acid deletion at the C-terminal conserved region) resulted in not only respiratory
deficiencies but also loss of mtDNA under normal mtDNA background. Surprisingly, V272L, but not other mutants, can rescue
the said deficiencies under intronless background. These results provide genetic evidence supporting the notion that the functional
requirements of SUV3 for degradosome activity and maintenance of mtDNA stability are separable. Furthermore, V272L mutants
and wild-type SUV3 associated with an active mtDNA replication origin and facilitated mtDNA replication, whereas K245A and
ΔCC failed to support mtDNA replication. These results indicate a direct role of SUV3 in maintaining mitochondrial genome
stability that is independent of intron turnover but requires the intact ATPase activity and the CC conserved region.
Journal of Biological Chemistry 11/2011; 286(44):38783-38794. · 4.77 Impact Factor
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ABSTRACT: Yeast SUV3 is a nuclear encoded mitochondrial RNA helicase that complexes with an exoribonuclease, DSS1, to function as an RNA degradosome. Inactivation of SUV3 leads to mitochondrial dysfunctions, such as respiratory deficiency; accumulation of aberrant RNA species, including excised group I introns; and loss of mitochondrial DNA (mtDNA). Although intron toxicity has long been speculated to be the major reason for the observed phenotypes, direct evidence to support or refute this theory is lacking. Moreover, it remains unknown whether SUV3 plays a direct role in mtDNA maintenance independently of its degradosome activity. In this paper, we address these questions by employing an inducible knockdown system in Saccharomyces cerevisiae with either normal or intronless mtDNA background. Expressing mutants defective in ATPase (K245A) or RNA binding activities (V272L or ΔCC, which carries an 8-amino acid deletion at the C-terminal conserved region) resulted in not only respiratory deficiencies but also loss of mtDNA under normal mtDNA background. Surprisingly, V272L, but not other mutants, can rescue the said deficiencies under intronless background. These results provide genetic evidence supporting the notion that the functional requirements of SUV3 for degradosome activity and maintenance of mtDNA stability are separable. Furthermore, V272L mutants and wild-type SUV3 associated with an active mtDNA replication origin and facilitated mtDNA replication, whereas K245A and ΔCC failed to support mtDNA replication. These results indicate a direct role of SUV3 in maintaining mitochondrial genome stability that is independent of intron turnover but requires the intact ATPase activity and the CC conserved region.
Journal of Biological Chemistry 09/2011; 286(44):38783-94. · 4.77 Impact Factor
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ABSTRACT: Short interfering RNAs (siRNAs) target specific mRNAs for their degradation mediated by RNA-induced silencing complex (RISC). Persistent activation of siRNA-RISC frequently leads to non-targeting toxicity. However, how cells mediate this stress remains elusive. In this communication, we found that the presence of non-targeting siRNA selectively induced the expression of an endoplasmic reticulum (ER)-resident protein, non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), but not other ER-stress proteins including GRP78, Calnexin and XBP1. Cells suffering from constant non-targeting siRNA stress grew slower and prolonged G1 phase, while NPGPx-depleted cells accumulated mature non-targeting siRNA and underwent apoptosis. Upon the stress, NPGPx covalently bound to exoribonuclease XRN2, facilitating XRN2 to remove accumulated non-targeting siRNA. These results suggest that NPGPx serves as a novel responder to non-targeting siRNA-induced stress in facilitating XRN2 to release the non-targeting siRNA accumulation.
Nucleic Acids Research 09/2011; 40(1):323-32. · 8.03 Impact Factor
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ABSTRACT: The spindle assemble checkpoint (SAC) is critical for accurate chromosome segregation. Hec1 contributes to chromosome segregation in part by mediating SAC signaling and chromosome alignment. However, the molecular mechanism by which Hec1 modulates checkpoint signaling and alignment remains poorly understood. We found that Hec1 serine 165 (S165) is preferentially phosphorylated at kinetochores. Phosphorylated Hec1 serine 165 (pS165) specifically localized to kinetochores of misaligned chromosomes, showing a spatiotemporal distribution characteristic of SAC molecules. Expressing an RNA interference (RNAi)-resistant S165A mutant in Hec1-depleted cells permitted normal progression to metaphase, but accelerated the metaphase-to-anaphase transition. The S165A cells were defective in Mad1 and Mad2 localization to kinetochores, regardless of attachment status. These cells often entered anaphase with lagging chromosomes and elicited increased segregation errors and cell death. In contrast, expressing S165E mutant in Hec1-depleted cells triggered defective chromosome alignment and severe mitotic arrest associated with increased Mad1/Mad2 signals at prometaphase kinetochores. A small portion of S165E cells eventually bypassed the SAC but showed severe segregation errors. Nek2 is the primary kinase responsible for kinetochore pS165, while PP1 phosphatase may dephosphorylate pS165 during SAC silencing. Taken together, these results suggest that modifications of Hec1 S165 serve as an important mechanism in modulating SAC signaling and chromosome alignment.
Molecular biology of the cell 08/2011; 22(19):3584-94. · 5.98 Impact Factor
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ABSTRACT: Proper assembly of mitotic spindles requires Hice1, a spindle-associated protein. Hice1 possesses direct microtubule binding activity at its N-terminal region and contributes to intraspindle microtubule nucleation as a subunit of the Augmin complex. However, whether microtubule binding activity of Hice1 is modulated by mitotic regulators remains unexplored. Here, we found that Aurora-A kinase, a major mitotic kinase, specifically binds to and phosphorylates Hice1. We identified four serine/threonine clusters on Hice1 that can be phosphorylated by Aurora-A in vitro. Of the four clusters, the Ser/Thr-17-21 cluster was the most critical for bipolar spindle assembly, whereas other phospho-deficient point mutants had a minimal effect on spindle assembly. Immunostaining with a phospho-Ser-19/20 phospho-specific antibody revealed that phosphorylated Hice1 primarily localizes to spindle poles during prophase to metaphase but gradually diminishes after anaphase. Consistently, the phospho-mimic 17-21E mutant reduced microtubule binding activity in vitro and diminished localization to spindles in vivo. Furthermore, expression of the 17-21E mutant led to decreased association of Fam29a, an Augmin component, with spindles. On the other hand, expression of the phospho-deficient 17-21A mutant permitted intraspindle nucleation but delayed the separation of early mitotic spindle poles and the timely mitotic progression. Taken together, these results suggest that Aurora-A modulates the microtubule binding activity of Hice1 in a spatiotemporal manner for proper bipolar spindle assembly.
Journal of Biological Chemistry 06/2011; 286(34):30097-106. · 4.77 Impact Factor
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ABSTRACT: As cells differentiate into tissues, the microenvironment that surrounds these cells must cooperate so that properly organized, growth-controlled tissues are developed and maintained. We asked whether substances produced from this collaboration might thwart malignant cells if they arise in the vicinity of normal tissues. Here, we identified six factors secreted by nonmalignant mammary epithelial cells (MECs) differentiating in three-dimensional laminin-rich gels that exert cytotoxic activity on breast cancer cells. Among these, interleukin-25 (IL-25/IL-17E) had the highest anticancer activity without affecting nonmalignant MECs. Apoptotic activity of IL-25 was mediated by differential expression of its receptor, IL-25R, which was expressed in high amounts in tumors from patients with poor prognoses but was low in nonmalignant breast tissue. In response to IL-25, the IL-25R on the surface of breast cancer cells activated caspase-mediated apoptosis. Thus, the IL-25/IL-25R signaling pathway may serve as a new therapeutic target for advanced breast cancer.
Science translational medicine 04/2011; 3(78):78ra31. · 7.80 Impact Factor
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ABSTRACT: It has been well documented that microenvironment consisting of stroma affects breast cancer progression. However, the mechanisms by which cancer cells and fibroblasts, the major cell type in stroma, interact with each other during tumor development remains to be elucidated. Here, we show that the human cancer-associated fibroblasts (CAFs) had higher activity in enhancing breast tumorigenecity compared to the normal tissue-associated fibroblasts (NAFs) isolated from the same patients. The expression level of hepatocyte growth factor (HGF) in these fibroblasts was positively correlated with their ability to enhance breast tumorigenesis in mice. Deprivation of HGF using a neutralizing antibody reduced CAF-mediated colony formation of human breast cancer cells, indicating that CAFs enhanced cancer cell colony formation mainly through HGF secretion. Co-culture with human breast cancer MDA-MB-468 cells in a transwell system enhanced NAFs to secret HGF as well as promote tumorigenecity. The newly gained ability of these "educated" NAFs became irreversible after continuing this process till fourth passage. These results suggested that breast cancer cells could alter the nature of its surrounding fibroblasts to secrete HGF to support its own progression through paracrine signaling.
PLoS ONE 01/2011; 6(1):e15313. · 4.09 Impact Factor
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ABSTRACT: RB plays an essential role in DNA damage-induced growth arrest and regulates the expression of several factors essential for DNA repair machinery. However, how RB coordinates DNA damage response through transcriptional regulation of genes involved in growth arrest remains largely unexplored. We examined whether RB can mediate the response to DNA damage through modulation of ZBRK1, a zinc finger-containing transcriptional repressor that can modulate the expression of GADD45A, a DNA damage response gene, to induce cell cycle arrest in response to DNA damage. We found that the ZBRK1 promoter contains an authentic E2F-recognition sequence that specifically binds E2F1, but not E2F4 or E2F6, together with chromatin remodeling proteins CtIP and CtBP to form a repression complex that suppresses ZBRK1 transcription. Furthermore, loss of RB-mediated transcriptional repression led to an increase in ZBRK1 transcript levels, correlating with increased sensitivity to ultraviolet (UV) and methyl methanesulfonate-induced DNA damage. Taken together, these results suggest that the RB·CtIP (CtBP interacting protein)/CtBP (C terminus-binding protein) /E2F1 complex plays a critical role in ZBRK1 transcriptional repression, and loss of this repression may contribute to cellular sensitivity of DNA damage, ultimately leading to carcinogenesis.
Journal of Biological Chemistry 10/2010; 285(43):33134-43. · 4.77 Impact Factor
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ABSTRACT: Cancer is responsible for one in eight deaths worldwide, with more than twelve million new cases diagnosed yearly. A large percentage of patients die after developing cancer despite aggressive treatment, indicating a need for new approaches to cancer therapy. The push for development of novel diagnostic and therapeutic agents has allowed translational cancer research to flourish. Genomic and proteomic technologies have generated an enormous amount of information critical to expanding our understanding of cancer biology. New research on the differences between normal and malignant cell biology has paved the way for the development of drugs targeted to specific biological molecules, potentially increasing antitumor efficacy while minimizing the toxicity to the patient that is seen with conventional therapeutics. Current targets in include regulators of cell cycle, angiogenesis, apoptosis, DNA repair, and growth factors and their receptors. Collaboration among researchers, clinicians, and pharmaceutical companies is vital to conducting clinical trials to translate laboratory findings into clinically applicable therapeutics. In this review, we discuss current therapeutic approaches and present an introduction to a wide range of topics undergoing investigation in an effort to highlight the importance of translational research in the development of clinically relevant therapeutic strategies.
American Journal of Translational Research 01/2010; 2(1):1-18.
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American Journal of Translational Research 01/2010; 2(4):458-62.
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Li-Fang Lin,
Chih-Hung Chuang,
Chien-Feng Li,
Ching-Chun Liao,
Chun-Pei Cheng,
Tian-Lu Cheng,
Meng-Ru Shen,
Joseph T Tseng,
Wen-Chang Chang, Wen-Hwa Lee,
Ju-Ming Wang
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ABSTRACT: The BRCA1-interacted transcriptional repressor ZBRK1 has been associated with antiangiogenesis, but direct evidence of a tumor suppressor role has been lacking. In this study, we provide evidence of such a role in cervical carcinoma. ZBRK1 levels in cervical tumor cells were significantly lower than in normal cervical epithelial cells. In HeLa cervical cancer cells, enforced expression inhibited malignant growth, invasion, and metastasis in a variety of in vitro and in vivo assays. Expression of the metalloproteinase MMP9, which is known to be an important driver of invasion and metastasis, was found to be inversely correlated with ZBRK1 in tumor tissues and a target for repression in tumor cells. Our findings suggest that ZBRK1 acts to inhibit me-tastasis of cervical carcinoma, perhaps by modulating MMP9 expression.
Cancer Research. 01/2010; 70:192-201.
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Li-Fang Lin,
Chih-Hung Chuang,
Chien-Feng Li,
Ching-Chun Liao,
Chun-Pei Cheng,
Tian-Lu Cheng,
Meng-Ru Shen,
Joseph T Tseng,
Wen-Chang Chang, Wen-Hwa Lee,
Ju-Ming Wang
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ABSTRACT: The BRCA1-interacted transcriptional repressor ZBRK1 has been associated with antiangiogenesis, but direct evidence of a tumor suppressor role has been lacking. In this study, we provide evidence of such a role in cervical carcinoma. ZBRK1 levels in cervical tumor cells were significantly lower than in normal cervical epithelial cells. In HeLa cervical cancer cells, enforced expression inhibited malignant growth, invasion, and metastasis in a variety of in vitro and in vivo assays. Expression of the metalloproteinase MMP9, which is known to be an important driver of invasion and metastasis, was found to be inversely correlated with ZBRK1 in tumor tissues and a target for repression in tumor cells. Our findings suggest that ZBRK1 acts to inhibit metastasis of cervical carcinoma, perhaps by modulating MMP9 expression.
Cancer Research 12/2009; 70(1):192-201. · 7.86 Impact Factor
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ABSTRACT: The high mobility group AT-hook 2 (HMGA2), a DNA architectural protein, is highly regulated during development and plays an important role in tumorigenesis. Indeed, HMGA2 was overexpressed in many different kinds of tumors. However, the mechanisms regulating HMGA2 expression remain elusive. Using microarray analysis, we found that HMGA2, along with a dozen of other genes, was co-repressed by ZBRK1, BRCA1, and CtIP. BRCA1 exerts its transcriptional repression activity through interaction with the transcriptional repressor ZBRK1 in the central domain, and with CtIP in the C-terminal BRCT domain. Here, we show that ZBRK1, BRCA1, and CtIP form a repression complex that coordinately regulates HMGA2 expression via a ZBRK1 recognition site in the HMGA2 promoter. Depletion of any of the proteins in this complex via adenoviral RNA interference in MCF10A mammary epithelial cells activates HMGA2 expression, resulting in increased colony formation in soft agar. Similarly, depletion of ZBRK1, or ectopic overexpression of HMGA2, in MCF10A cells induces abnormal acinar size with increased cell number and inhibits normal acinar formation. Consistently, many BRCA1-deficient mouse breast tumors express higher levels of HMGA2 than BRCA1-proficient tumors. These results suggest that activation of HMGA2 gene expression through derepression of the ZBRK1/BRCA1/CtIP complex is a significant step in accelerating breast tumorigenesis.
Journal of Biological Chemistry 12/2009; 285(7):4464-71. · 4.77 Impact Factor
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ABSTRACT: Previous studies have stipulated Hec1 as a conserved kinetochore component critical for mitotic control in part by directly binding to kinetochore fibers of the mitotic spindle and by recruiting spindle assembly checkpoint proteins Mad1 and Mad2. Hec1 has also been reported to localize to centrosomes, but its function there has yet to be elucidated. Here, we show that Hec1 specifically colocalizes with Hice1, a previously characterized centrosomal microtubule-binding protein, at the spindle pole region during mitosis. In addition, the C-terminal region of Hec1 directly binds to the coiled-coil domain 1 of Hice1. Depletion of Hice1 by small interfering RNA (siRNA) reduced levels of Hec1 in the cell, preferentially at centrosomes and spindle pole vicinity. Reduction of de novo microtubule nucleation from mitotic centrosomes can be observed in cells treated with Hec1 or Hice1 siRNA. Consistently, neutralization of Hec1 or Hice1 by specific antibodies impaired microtubule aster formation from purified mitotic centrosomes in vitro. Last, disruption of the Hec1/Hice1 interaction by overexpressing Hice1DeltaCoil1, a mutant defective in Hec1 interaction, elicited abnormal spindle morphology often detected in Hec1 and Hice1 deficient cells. Together, the results suggest that Hec1, through cooperation with Hice1, contributes to centrosome-directed microtubule growth to facilitate establishing a proper mitotic spindle.
Molecular biology of the cell 09/2009; 20(22):4686-95. · 5.98 Impact Factor
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ABSTRACT: Efficient turnover of unnecessary and misfolded RNAs is critical for maintaining the integrity and function of the mitochondria. The mitochondrial RNA degradosome of budding yeast (mtEXO) has been recently studied and characterized; yet no RNA degradation machinery has been identified in the mammalian mitochondria. In this communication, we demonstrated that purified human SUV3 (suppressor of Var1 3) dimer and polynucleotide phosphorylase (PNPase) trimer form a 330-kDa heteropentamer that is capable of efficiently degrading double-stranded RNA (dsRNA) substrates in the presence of ATP, a task the individual components cannot perform separately. The configuration of this complex is similar to that of the core complex of the E. coli RNA degradosome lacking RNase E but very different from that of the yeast mtEXO. The hSUV3-hPNPase complex prefers substrates containing a 3' overhang and degrades the RNA in a 3'-to-5' directionality. Deleting a short stretch of amino acids (positions 510-514) compromises the ability of hSUV3 to form a stable complex with hPNPase to degrade dsRNA substrates but does not affect its helicase activity. Furthermore, two additional hSUV3 mutants with abolished helicase activity because of disrupted ATPase or RNA binding activities were able to bind hPNPase. However, the resulting complexes failed to degrade dsRNA, suggesting that an intact helicase activity is essential for the complex to serve as an effective RNA degradosome. Taken together, these results strongly suggest that the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA and may be the long sought RNA-degrading complex in the mammalian mitochondria.
Journal of Biological Chemistry 07/2009; 284(31):20812-21. · 4.77 Impact Factor
