Skip to main content
NCBI home page
Cell Cycle logoLink to Cell Cycle
. 2016 May 6;15(14):1821–1829. doi: 10.1080/15384101.2016.1183845

RNA helicase SACY-1 is required for longevity caused by various genetic perturbations in Caenorhabditis elegans

Mihwa Seo a, Sangsoon Park a, Hong Gil Nam d,e,✉, Seung-Jae V Lee a,b,c,✉
PMCID: PMC4968901  PMID: 27153157

ABSTRACT

RNA helicases, which unwind RNAs, are essential for RNA metabolism and homeostasis. However, the roles of RNA helicases in specific physiological processes remain poorly understood. We recently reported that an RNA helicase, HEL-1, promotes long lifespan conferred by reduced insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) in Caenorhabditis elegans. We also showed that HEL-1 induces the expression of longevity genes by physically interacting with Forkhead box O (FOXO) transcription factor. Thus, the HEL-1 RNA helicase appears to regulate lifespan by specifically activating FOXO in IIS. In the current study, we report another longevity-promoting RNA helicase, Suppressor of ACY-4 sterility 1 (SACY-1). SACY-1 contributed to the longevity of daf-2/insulin/IGF-1 receptor mutants. Unlike HEL-1, SACY-1 was also required for the longevity due to mutations in genes involved in non-IIS pathways. Thus, SACY-1 appears to function as a general longevity factor for various signaling pathways, which is different from the specific function of HEL-1.

KEYWORD: Aging, daf-2, C. elegans, HEL-1, insulin/IGF-1 signaling, RNA helicase, SACY-1

Introduction

RNA is an essential cellular component that participates in various key aspects of biological processes, including the transcription and translation of genetic information. To execute these biological functions, RNA must adopt the appropriate structure for each process. RNA helicases, which unwind RNAs that have intra- or inter-molecular double-stranded regions, are responsible for remodeling RNA to ensure the formation of appropriate structure.(For a review see ref.1) RNA helicases are highly conserved from bacteria to humans and are even found in many viruses.2,3

RNA helicases are classified into 6 superfamilies (SFs) based on their sequences and structural and functional features. Eukaryotic RNA helicases are classified into SF1 and SF2.(For a review see ref.1) These RNA helicase SFs are subdivided into several families. The DEAD-box RNA helicase family, which belongs to SF2, is the largest among them. There are 37 members of the DEAD-box RNA helicase family in humans.(For reviews see refs.4-6) DEAD-box RNA helicases contain 12 highly conserved motifs, among which the Asp-Glu-Ala-Asp (DEAD) motif is the most representative.(For a review see ref.5) DEAD-box RNA helicases unwind and remodel RNA using energy obtained from ATP hydrolysis.(For reviews see refs.7,8) RNA helicases also regulate various steps of essential RNA-metabolic processes, including RNA strand annealing, RNA clamping, and disruption of RNA–protein interaction.(For reviews see ref.7) Emerging evidence indicates that DEAD-box RNA helicases are involved in other physiological processes, including post-translational modification and metabolite sensing.(For reviews see refs.7,9) Our recent study indicates that RNA helicases can also regulate organismal lifespan.10

Insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway is one of the most evolutionarily conserved pathways that regulate lifespan in animals.(For a review see ref.11) Two of the most well-studied components of the IIS pathway in Caenorhabditis elegans are DAF-2, an insulin/IGF-1 receptor ortholog, and the transcription factor DAF-16/Forkhead box O (FOXO) transcription factor.12-15 Activation of the IIS pathway leads to the phosphorylation of DAF-16, which prevents its translocation to the nucleus and the subsequent transcription of its target genes.16-20 Reduction of the IIS activity by daf-2 mutations doubles the lifespan of C. elegans, and this effect is mediated by the activation of DAF-16/FOXO.15,17-19

Prior to our previous study,10 implication of RNA helicases in the aging process was restricted to cellular senescence.(For a review see ref.21) DHX36, a DExH-box RNA helicase, and DDX39A/UAP56/BAT1, the human ortholog of C. elegans HEL-1, have been shown to be involved in telomere maintenance.22,23 To our knowledge, our previous study was the first mechanistic study to demonstrate the regulation of organismal aging by an RNA helicase.10 We performed a large-scale lifespan screen by knocking down 78 putative RNA helicases in C. elegans, and found that 11 of them rather specifically affected the lifespan of wild-type or that of daf-2 mutants. These data suggest that many RNA helicases play crucial roles in lifespan regulation in C. elegans. Among the 11 RNA helicases, we focused on HEL-1, a C. elegans DEAD-box RNA helicase that contributes to the longevity of daf-2 mutants.10 HEL-1 regulates the transcriptional activity of DAF-16 via physical interaction. This interaction leads to the induction of downstream target genes that extend lifespan in animals with reduced IIS.

Our genetic screen also identified suppressor of acy-4(-)/adenylyl cyclase-4 sterility 1 (sacy-1), which encodes the ortholog of human DEAD-box RNA helicase DDX41, as a candidate lifespan regulator of IIS mutants.10 Our screening results are consistent with those of a previous genetic screen which showed that sacy-1 is required for the longevity of daf-2 mutants.24 Although sacy-1 is known to negatively regulate oocyte meiotic maturation, and is required for sex determination and gamete maintenance,25 its role in aging was unknown. In this current report, we show that sacy-1 is required for the long lifespan of animals with various longevity pathway mutations, including IIS, sensory neuron, germline, mitochondrial-respiration, and dietary-restriction mimetic mutations. Together with the previous report regarding HEL-1, the current study suggests that DEAD-box RNA helicases regulate lifespan by mediating distinct physiological processes in C. elegans. This study also supports the functional diversity of DEAD-box RNA helicases. As RNA helicases as well as the IIS pathway are evolutionarily well conserved, our study has a potential for extending our understanding of the diverse functions of RNA helicases and mammalian aging.

Results

We and others previously reported that SACY-1 was required for the longevity of daf-2 mutants.10,24 SACY-1 contains several domains, including a DEAD-box domain, helicase C domain, and the zinc finger (zf-CCHC) domain (Fig. 1A). The amino acid sequences (Fig. 1B) of SACY-1 homologs are well conserved from yeast to human; the amino acid sequence of C. elegans SACY-1 shows 43%, 54%, and 60% identity to those of yeast DBP2, Drosophila abstrakt, and mouse and human DDX41, respectively (Fig. 1B and C). The predicted structure of the helicase domain of C. elegans SACY-1 also displays a strong similarity to that of human DDX41 (Fig. 1D).

Figure 1.

Figure 1.

Open in a new tab

The sequence and structural conservation of SACY-1 homologs. (A) A schematic diagram of SACY-1 showing its functional domains, including a DEAD-box domain, a helicase C domain, and a zinc finger (zf-CCHC) domain. (B) Alignment of the amino acid sequences of C. elegans SACY-1 and its homologs. The amino acid sequence of C. elegans SACY-1 was compared with those of yeast DBP2 (43% identity), Drosophila abstrakt (54% identity), mouse DDX41 (60% identity), and human DDX41 (60% identity). The symbol “*” indicates an identical residue, “:” indicates a residue that has conserved amino acids with strong similarities, and “.” indicates a residue that has conserved amino acids with weak similarities. Gray bars indicate the degrees of relative conservation at each residue. (C) A phylogenetic tree of SACY-1 in various species, which was generated and visualized using Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo/)39 and TreeView,41 respectively. (D) The superimposed structure of the helicase domain of C. elegans SACY-1 (residues 415–573) and human DDX41 (residues 406–565).42

We found that sacy-1 RNAi treatment for the entire life of an animal (whole-life RNAi) had a larger lifespan-decreasing effect on daf-2 mutants than on wild-type animals (Fig. S1A). We then performed lifespan assays using animals that experienced sacy-1 RNAi only during adulthood (adult-only RNAi) to eliminate possible developmental defects that are caused by whole-life RNAi. We observed that adult-only sacy-1 RNAi also greatly shortened the lifespan of daf-2 mutants, while having a small effect on that of wild-type animals (Fig. 2A). We confirmed that sacy-1 RNAi decreased the expression level of sacy-1 by using qRT-PCR (Fig. S1C). Consistent with the data using sacy-1 RNAi, sacy-1(tn1835) mutations decreased the lifespan-extending effect of daf-2 RNAi (Fig. 2B). This result is consistent with those of previous reports, including ours.10,24 We then tested whether SACY-1 acts together with DAF-16/FOXO, a key downstream transcription factor in IIS, using daf-16 mutants and daf-16; daf-2 double mutants. sacy-1 RNAi had a small or no effect on the lifespan of daf-16 mutant (Fig. 2C) or daf-16; daf-2 double mutant (Fig. 2D). We then found that the expression level of a GFP reporter for sod-3, an established DAF-16 target, was not affected by sacy-1 RNAi (Fig 2E–2I); this result is also consistent with a previous report.24 These data indicate that SACY-1 may act with DAF-16 at the downstream of DAF-2 to influence lifespan, but independently of the transcriptional activity of DAF-16. Overall, in agreement with our previous report, we conclude that sacy-1 is required for lifespan extension by reduced IIS.

Figure 2.

Figure 2.

Open in a new tab

sacy-1 is required for the longevity conferred by reduced insulin/IGF-1 signaling. (A, B) The lifespan-shortening effects of adult-only sacy-1 RNAi on daf-2(e1370) [daf-2(-)] and wild-type worms. (B) sacy-1(tn1835) [sacy-1(-)] mutations suppressed the longevity conferred by daf-2 RNAi. (C, D) The effects of sacy-1 RNAi on the lifespans of daf-16(mu86) [daf-16(-)] (C) and daf-16(mu86); daf-2(e1370) [daf-16(-); daf-2(-)] (D) mutants. See Tables S1 for individual lifespan values and statistical analysis. (E-H) The GFP expression level of sod-3:gfp was not influenced by sacy-1 RNAi in both wild-type and daf-2(e1370) (daf-2(-)) animals. Scale bars indicate 100 μm. (I) Quantification of data in panels E-H (N ≥ 18, triplicate). Error bars indicate SEM. daf-16 RNAi was used as a positive control. Day1 adult stage worms were used for panels E-I.

Stress resistance in C. elegans is generally associated with longevity.(For reviews see refs.11,26) Long-lived daf-2 mutants display resistance to diverse stresses, including oxidative stress,27 heat stress,28,29 and pathogenic bacterial infection.30 Therefore, we performed these stress resistance assays upon knocking down sacy-1. Unexpectedly, we found that sacy-1 mutation and sacy-1 RNAi significantly enhanced the resistance against oxidative stress caused by daf-2 RNAi and daf-2 mutations, respectively (Figs. 3A and S1B). sacy-1 RNAi did not affect thermotolerance (Fig. 3B), or survival upon infection with the pathogenic bacteria Pseudomonas aeruginosa (PA14) (Fig. 3C) in daf-2 mutants. These data suggest that sacy-1 contributes to the longevity of daf-2 mutants through a mechanism independent of these resistance phenotypes.

Figure 3.

Figure 3.

Open in a new tab

The role of sacy-1 in the stress resistance or reproductive span of daf-2 mutants. The effects of sacy-1 RNAi on the resistance against oxidative stress (A), heat stress (B), and pathogenic bacteria PA14 (Pseudomonas aeruginosa) (C) in daf-2(e1370) [daf-2(-)] and wild-type animals. (D) Reproductive span of wild-type and daf-2 mutants was indiscriminately decreased by sacy-1 RNAi. See Tables S2 for individual survival values and statistical analysis.

Previously, SACY-1 was shown to be required for the gamete maintenance.25 Thus, we measured the reproductive span of wild-type and daf-2 mutants upon treating with sacy-1 RNAi only during adulthood. We found that sacy-1 RNAi nonspecifically decreased the reproductive span of both wild-type and daf-2(e1370) animals (Fig. 3D). These data suggest that the functions of SACY-1 in the regulation of daf-2(e1370) longevity are independent of reproductive aging.

Next, we asked whether the function of SACY-1 in longevity is specific to the IIS pathway or general to other pathways that regulate aging. To this end, we knocked down sacy-1 in various long-lived mutants, including sensory-defective osm-5(p813), mitochondrial respiration-defective isp-1(qm150), reproduction-defective glp-1(e2141), and dietary restriction mimetic eat-2(ad1116) mutants. We found that treatment with sacy-1 RNAi for whole life or only during adulthood had larger lifespan-decreasing effects on the long lifespan of osm-5(p813), isp-1(qm150), or glp-1(e2141) mutants than on that of wild-type (Fig. 4A–C and S2A-S2B). However, the longevity-suppressing effect of sacy-1 RNAi was greatly reduced when sacy-1 was knocked down only during adulthood on eat-2(ad1116) compared to that of the whole-life sacy-1 RNAi (Figs. 4D and S2C). The lifespan-shortening effects of sacy-1 RNAi on these mutants were comparable to those on daf-2 mutants. Thus, SACY-1 appears to be a rather general regulator of longevity, which is distinct from the specific requirement of HEL-1 for IIS pathway-mediated longevity.

Figure 4.

Figure 4.

Open in a new tab

General requirement of sacy-1 for long lifespan in various mutants. The lifespan-shortening effects of adult-only sacy-1 RNAi on sensory neuron-defective osm-5(p813) [osm-5(-)] (A), mitochondrial respiration-defective isp-1(qm150) [isp-1(-)] (B), germline-deficient glp-1(e2141) [glp-1(-)] (C), and dietary restriction mimetic eat-2(ad1116) [eat-2(-)] (D) mutants. See Tables S1 for individual lifespan values and statistical analysis.

Discussion

RNA helicases are evolutionarily well-conserved enzymes that regulate diverse processes within RNA biology. However, the role of RNA helicases in aging remains poorly understood. In this study, we investigated the function of SACY-1 in the regulation of lifespan in C. elegans. We found that the RNA helicase SACY-1 contributes to the longevity of various long-lived mutants. The general requirement of SACY-1 for longevity is different from that of HEL-1, which is specifically required for the longevity caused by reduced IIS. Our data regarding HEL-1 and SACY-1 reflect the diverse characteristics of RNA helicases in various physiological processes.

In which tissues does sacy-1 function to regulate lifespan? We found that SACY-1::GFP25 was localized to the nuclei of neurons, hypodermis, intestine and germ cells (Fig. 5A–D). It will be crucial to test whether any of these tissues are important for the effects of SACY-1 on longevity by generating and characterizing tissue-specific sacy-1 RNAi and transgenic animals in future studies.

Figure 5.

Figure 5.

Open in a new tab

The expression pattern of SACY-1::GFP. SACY-1::GFP was expressed in the nuclei of cells in neurons (A), the intestine (B), the hypodermis (C) and the germline (D) (N = 5). Arrows indicate the nuclei of cells in each tissue. L4 stage animals were used for this Figure. Scale bars indicate 50 μm.

The biological functions of DDX41, the human homolog of C. elegans sacy-1, have been widely studied. Mutations in DDX41 are associated with myelodysplastic (MDS)/acute myeloid leukemia (AML) syndrome.31 This suggests that DDX41 functions as a tumor suppressor for MDS/AML. DDX41-deficient cells display pronounced splicing defects, and DDX41 directly interacts with spliceosomal components.31 Therefore, DDX41 is likely to be crucial for the precise splicing of mRNAs to maintain proper RNA physiology. Since SACY-1 and DDX41 share a high sequence similarity, it seems likely that SACY-1 is also a component of spliceosome and may affect the splicing of pre-mRNAs of longevity-assuring genes in C. elegans. Thus, future studies on how the RNA helicase activity of SACY-1 functions in pre-mRNA splicing will provide valuable insights into the mechanisms by which SACY-1 regulates lifespan.

DDX41 is also well known for its role in antiviral innate immunity.(For a review see ref.32) DDX41 acts as a pattern recognition receptor that recognizes pathogen-associated molecular patterns (PAMPs), especially double-stranded DNA and cyclic di-nucleotides.33-36 Upon binding to these PAMPs, DDX41 triggers the activation of transcription factors such as interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB).33,35,36 These transcription factors induce the secretion of type I interferon to defend against viruses. In contrast, sacy-1 was not required for resistance against pathogenic bacteria in C. elegans in our analysis. It will be interesting to test whether sacy-1 is required for viral immunity in C. elegans in the future.

To date, the molecular functions of RNA helicases have been extensively studied in vitro and for early developmental processes; yet, their roles in organismal aging have been underexplored. Our work on RNA helicases, such as HEL-1 and SACY-1, is part of a pioneering effort that has demonstrated the tight association of RNA helicases with animal longevity. In particular, our study implies that RNA helicases influence lifespan by acting through both specific and general signaling pathways. Because RNA helicases are evolutionarily well conserved, our study on C. elegans raises the possibility that RNA helicases are important lifespan regulators in mammals.

Materials and methods

Strains

All strains were maintained at 20°C. Some C. elegans strains used in this study were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources. The following C. elegans strains were used: N2 wild-type, CF1041 daf-2(e1370) III outcrossed 6 times to N2, CF1085 daf-16(mu86) I; daf-2(e1370) III, CF1042 daf-16(mu86) I, CF2553 osm-5(p813) X outcrossed 3 times to N2, CF2172 isp-1(qm150) IV outcrossed 3 times to N2, and IJ173 eat-2(ad1116) II outcrossed 4 times to N2. DG3430 sacy-1(tn1385) I, CF1903 glp-1(e2141) III, CF1553 muIs84[sod-3p::gfp], CF1580 daf-2(e1370) III; muIs84[sod-3p::gfp], DG3485 sacy-1(tm5503) I; tnEx159[sacy-1p::gfp::sacy-1; unc-119(+)].

Schematic domain structure of SACY-1

The protein domain information was obtained from SMART (http://smart.embl-heidelberg.de/).37 IBS 1.0 program was used for illustration of SACY-1 domains.38

Sequence homology alignment

Protein sequences were obtained from the National Center for Biotechnology Information. Sequence homology was determined using Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo/)39 and ClustalX software.40

Generation of phylogenic tree

A phylogenetic tree showing sequence similarities among SACY-1 and its homologs in several organisms was generated by using Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo/)39 and re-visualized using TreeView.41

Modeling of SACY-1 protein structure

Amino acid sequences of C. elegans SACY-1 was used as a query sequence and the crystal structure of the human DDX41 helicase domain (PDB ID: 2P6N)42 was used as a template for the SWISS-MODEL alignment algorithm (http://swissmodel.expasy.org/)43 to model the structure of the helicase domain of SACY-1. PyMOL software was used to visualize the proteins (http://www.pymol.org/).44

Lifespan assays

Lifespan assays were performed as previously described,45,46 with some modifications. A sacy-1 RNAi clone was obtained from the Marc Vidal library47 and verified by sequencing and BLAST48 analysis prior to use. Gravid adults were placed on plates seeded with bacteria expressing control double stranded RNA (control RNAi) or sacy-1 double stranded RNA (sacy-1 RNAi), and the progeny were allowed to develop to the L4 stage. These L4-stage worms were then transferred onto specific RNAi plates. Day1 adult-stage worms were treated with 5 μM 5-fluoro-2′-deoxyuridine (FUdR; Sigma, F0503). All lifespan assays were performed at 20°C. A total of > 75 worms were used for each condition. Dead worms were removed from the plates and scored as dead. Worms that crawled off and those that displayed internal hatching or vulval extrusion were censored but included in the subsequent statistical analysis. OASIS (online application of survival analysis, http://sbi.postech.ac.kr/oasis) was used for statistical analysis,49 and the log-rank (Mantel–Cox) test was used to calculate P values.

Fluorescence imaging of sod-3p::gfp and sacy-1::gfp transgenic worms

sod-3p::gfp or sacy-1::gfp transgenic animals were synchronized on specific RNAi- or OP50-seeded plates. Fluorescence images were captured by using an AxioCam HRc CCD digital camera (Zeiss Corporation) with a Zeiss Axio Scope A1 compound microscope (Zeiss Corporation).

Oxidative stress resistance assays

Oxidative stress resistance assays were performed as previously described,50 with modifications. Briefly, eggs were synchronized on control or sacy-1 RNAi plates by allowing gravid adult worms to lay eggs for 12–14 h. After the eggs developed to day1 adults, worms were moved onto plates that contained 7.5 mM tert-Butyl hydroperoxide solution (Sigma, B2633) and 5 μM FUdR. The survival of the animals was examined at least once a day. The oxidative stress resistance assays were repeated twice, independently. OASIS was used for statistical analysis, and P values were calculated using the log-rank (Mantel–Cox method) test.49

Thermotolerance assays

Thermotolerance assays were performed as previously described,51 with minor modifications. Synchronized day-1 adults on control or sacy-1 RNAi plates were transferred from a 20°C incubator to a 35°C incubator for heat treatment, and their survival was then assessed every 3–4 h. The survival assays were repeated twice, independently. OASIS was used for statistical analysis, and P values were calculated by using the log-rank (Mantel–Cox method) test.49

Pathogen resistance assays

Pathogen resistance assays were performed as previously described,52 with minor modifications. Day1 adult worms were placed on plates containing cultured Pseudomonas aeruginosa (PA14) with 50 μM FUdR, and the worms were transferred to new PA14 plates containing 50 μM FUdR the next day. Survival was assessed at least twice a day. OASIS was used for statistical analysis, and P values were calculated using the log-rank (Mantel–Cox method) test.49

Reproductive span assays

Reproductive span assays were performed as described previously with some modifications.10 Synchronized individual L4-stage worms were transferred to new plates until they stopped laying eggs at least for 2 d. Reproductive span was recorded as the last day when a worm produced viable progeny.

Quantitative RT-PCR analysis

Synchronized day1 adult worms were prepared using a bleaching method for harvesting and RNA Isoplus (Takara, 9109) was used for RNA extraction. RNA was converted to cDNA by using reverse transcription system (Promega, A5003) with oligodT primers. cDNA was used for quantitative PCR for measuring the expression of each specific gene with SYBR green dye (Applied Biosystems, 4367659) by using StepOne Real Time PCR System (Applied Biosystems, 4376357) and analyzed by using comparative CT method. ama-1 mRNA level was used as a control for normalization. The following are oligonucleotides used for the quantitative RT-PCR.

List of oligonucleotides used for the quantitative RT-PCR

  • ama-1-F-TGGAACTCTGGAGTCACACC

  • ama-1-R-CATCCTCCTTCATTGAACGG

  • sacy-1-F-CGACGATGGTGGTTTCTGA

  • sacy-1-R-TAGATTGAGATACAATGTATG

Supplementary Material

1183845_Supplemental_Material.zip

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

Caenorhabditis Genetics Center provided some of the C. elegans strains used in this study. We thank all the members of Lee and Nam laboratories for their help and discussion.

Funding

This work was supported by the Institute for Basic Science (IBS-R013-D1) to H.G.N. and, NRF-2013R1A1A2014754 funded by the Korean Government (MSIP) through the National Research Foundation of Korea (NRF), and a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2337) to S-J.V.L.

References

  • [1].Jankowsky E. RNA helicases at work: binding and rearranging. Trends Biochem Sci 2011; 36:19-29; PMID:20813532; http://dx.doi.org/ 10.1016/j.tibs.2010.07.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Anantharaman V, Koonin EV, Aravind L. Comparative genomics and evolution of proteins involved in RNA metabolism. Nucleic Acids Res 2002; 30:1427-64; PMID:11917006; http://dx.doi.org/ 10.1093/nar/30.7.1427 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Gorbalenya AE, Koonin EV. Helicases: amino acid sequence comparisons and structure-function relationships. Curr Opin Struct Biol 1993; 3:419-29; http://dx.doi.org/ 10.1016/S0959-440X(05)80116-2 [DOI] [Google Scholar]
  • [4].Fairman-Williams ME, Guenther UP, Jankowsky E. SF1 and SF2 helicases: family matters. Curr Opin Struct Biol 2010; 20:313-24; PMID:20456941; http://dx.doi.org/ 10.1016/j.sbi.2010.03.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Linder P, Fuller-Pace FV. Looking back on the birth of DEAD-box RNA helicases. Biochim Biophys Acta 2013; 1829:750-5; PMID:23542735; http://dx.doi.org/ 10.1016/j.bbagrm.2013.03.007 [DOI] [PubMed] [Google Scholar]
  • [6].Linder P, Jankowsky E. From unwinding to clamping—the DEAD box RNA helicase family. Nat Rev Mol Cell Biol 2011; 12:505-16; PMID:21779027; http://dx.doi.org/ 10.1038/nrm3154 [DOI] [PubMed] [Google Scholar]
  • [7].Putnam AA, Jankowsky E. DEAD-box helicases as integrators of RNA, nucleotide and protein binding. Biochim Biophys Acta 2013; 1829:884-93; PMID:23416748; http://dx.doi.org/ 10.1016/j.bbagrm.2013.02.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Russell R, Jarmoskaite I, Lambowitz AM. Toward a molecular understanding of RNA remodeling by DEAD-box proteins. RNA Biology 2013; 10:44-55; PMID:22995827; http://dx.doi.org/ 10.4161/rna.22210 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Gustafson EA, Wessel GM. DEAD-box helicases: posttranslational regulation and function. Biochem Biophys Res Commun 2010; 395:1-6; PMID:20206133; http://dx.doi.org/ 10.1016/j.bbrc.2010.02.172 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Seo M, Seo K, Hwang W, Koo HJ, Hahm JH, Yang JS, Han SK, Hwang D, Kim S, Jang SK, et al.. RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans. Proc Natl Acad Sci U S A 2015; 112:E4246-55; PMID:26195740; http://dx.doi.org/ 10.1073/pnas.1505451112 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Kaletsky R, Murphy CT. The role of insulin/IGF-like signaling in C. elegans longevity and aging. Dis Model Mech 2010; 3:415-9; PMID:20354111; http://dx.doi.org/ 10.1242/dmm.001040 [DOI] [PubMed] [Google Scholar]
  • [12].Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science (New York, NY) 1997; 277:942-6; PMID:9252323; http://dx.doi.org/ 10.1126/science.277.5328.942 [DOI] [PubMed] [Google Scholar]
  • [13].Lin K, Dorman JB, Rodan A, Kenyon C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science (New York, NY) 1997; 278:1319-22; PMID:9360933; http://dx.doi.org/ 10.1126/science.278.5341.1319 [DOI] [PubMed] [Google Scholar]
  • [14].Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 1997; 389:994-9; PMID:9353126; http://dx.doi.org/ 10.1038/40194 [DOI] [PubMed] [Google Scholar]
  • [15].Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature 1993; 366:461-4; PMID:8247153; http://dx.doi.org/ 10.1038/366461a0 [DOI] [PubMed] [Google Scholar]
  • [16].Cahill CM, Tzivion G, Nasrin N, Ogg S, Dore J, Ruvkun G, Alexander-Bridges M. Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and function via 14-3-3-dependent and 14-3-3-independent pathways. J Biol Chem 2001; 276:13402-10; PMID:11124266; http://dx.doi.org/ 10.1074/jbc.M010042200 [DOI] [PubMed] [Google Scholar]
  • [17].Henderson ST, Johnson TE. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 2001; 11:1975-80; PMID:11747825; http://dx.doi.org/ 10.1016/S0960-9822(01)00594-2 [DOI] [PubMed] [Google Scholar]
  • [18].Lee RY, Hench J, Ruvkun G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol 2001; 11:1950-7; PMID:11747821; http://dx.doi.org/ 10.1016/S0960-9822(01)00595-4 [DOI] [PubMed] [Google Scholar]
  • [19].Lin K, Hsin H, Libina N, Kenyon C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 2001; 28:139-45; PMID:11381260; http://dx.doi.org/ 10.1038/88850 [DOI] [PubMed] [Google Scholar]
  • [20].Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 2003; 424:277-83; PMID:12845331; http://dx.doi.org/ 10.1038/nature01789 [DOI] [PubMed] [Google Scholar]
  • [21].Steimer L, Klostermeier D. RNA helicases in infection and disease. RNA Biol 2012; 9:751-71; PMID:22699555; http://dx.doi.org/ 10.4161/rna.20090 [DOI] [PubMed] [Google Scholar]
  • [22].Sexton AN, Collins K. The 5′ guanosine tracts of human telomerase RNA are recognized by the G-quadruplex binding domain of the RNA helicase DHX36 and function to increase RNA accumulation. Mol Cell Biol 2011; 31:736-43; PMID:21149580; http://dx.doi.org/ 10.1128/MCB.01033-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Yoo HH, Chung IK. Requirement of DDX39 DEAD box RNA helicase for genome integrity and telomere protection. Aging cell 2011; 10:557-71; PMID:21388492; http://dx.doi.org/ 10.1111/j.1474-9726.2011.00696.x [DOI] [PubMed] [Google Scholar]
  • [24].Samuelson AV, Carr CE, Ruvkun G. Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. Genes Dev 2007; 21:2976-94; PMID:18006689; http://dx.doi.org/ 10.1101/gad.1588907 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Kim S, Govindan JA, Tu ZJ, Greenstein D. SACY-1 DEAD-Box helicase links the somatic control of oocyte meiotic maturation to the sperm-to-oocyte switch and gamete maintenance in Caenorhabditis elegans. Genetics 2012; 192:905-28; PMID:22887816; http://dx.doi.org/ 10.1534/genetics.112.143271 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Murphy CT, Hu PJ. Insulin/insulin-like growth factor signaling in C. elegans. WormBook : the online review of C. elegans biology 2013:1-43; PMID:24395814; http://dx.doi.org/ 10.1895/wormbook.1.164.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Honda Y, Honda S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. The FASEB Journal 1999; 13:1385-93; PMID:10428762 [PubMed] [Google Scholar]
  • [28].Gems D, Sutton AJ, Sundermeyer ML, Albert PS, King KV, Edgley ML, Larsen PL, Riddle DL. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics 1998; 150:129-55; PMID:9725835 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Lithgow GJ, White TM, Melov S, Johnson TE. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A 1995; 92:7540-4; PMID:7638227; http://dx.doi.org/ 10.1073/pnas.92.16.7540 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Garsin DA, Villanueva JM, Begun J, Kim DH, Sifri CD, Calderwood SB, Ruvkun G, Ausubel FM. Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science (New York, NY) 2003; 300:1921; PMID:12817143 [DOI] [PubMed] [Google Scholar]
  • [31].Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, Singh J, Padgett RA, Gu X, Phillips JG. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 2015; 27:658-70; PMID:25920683; http://dx.doi.org/ 10.1016/j.ccell.2015.03.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Fullam A, Schröder M. DExD/H-box RNA helicases as mediators of anti-viral innate immunity and essential host factors for viral replication. Biochi Biophys Acta 2013; 1829:854-65; PMID:NOT_FOUND; http://dx.doi.org/ 10.1016/j.bbagrm.2013.03.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Parvatiyar K, Zhang Z, Teles RM, Ouyang S, Jiang Y, Iyer SS, Zaver SA, Schenk M, Zeng S, Zhong W. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol 2012; 13:1155-61; PMID:23142775; http://dx.doi.org/ 10.1038/ni.2460 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Quynh NT, Hikima J-i, Kim Y-r, Fagutao FF, Kim MS, Aoki T, Jung TS. The cytosolic sensor, DDX41, activates antiviral and inflammatory immunity in response to stimulation with double-stranded DNA adherent cells of the olive flounder, Paralichthys olivaceus. Fish Shellfish Immunol 2015; 44:576-83; PMID:25776036; http://dx.doi.org/ 10.1016/j.fsi.2015.03.008 [DOI] [PubMed] [Google Scholar]
  • [35].Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu Y-J. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 2011; 12:959-65; PMID:21892174; http://dx.doi.org/ 10.1038/ni.2091 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Lee K-G, Kim SS-Y, Kui L, Voon DC-C, Mauduit M, Bist P, Bi X, Pereira NA, Liu C, Sukumaran B. Bruton's tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response. Cell Rep 2015; 10:1055-65; PMID:25704810; http://dx.doi.org/ 10.1016/j.celrep.2015.01.039 [DOI] [PubMed] [Google Scholar]
  • [37].Letunic I, Doerks T, Bork P. SMART: recent updates, new developments and status in 2015. Nucleic Acids Res 2015; 43:D257-D60; PMID:25300481; http://dx.doi.org/ 10.1093/nar/gku949 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Liu W, Xie Y, Ma J, Luo X, Nie P, Zuo Z, Lahrmann U, Zhao Q, Zheng Y, Zhao Y. IBS: an illustrator for the presentation and visualization of biological sequences. Bioinformatics (Oxford, England) 2015; 31:3359-61; PMID:26069263; http://dx.doi.org/ 10.1093/bioinformatics/btv362 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Sievers F, Higgins DG. Clustal omega. Curr Protoc Bioinformatics 2014; 48:3.13.1-16; PMID:25501942 [DOI] [PubMed] [Google Scholar]
  • [40].Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, et al.. Clustal W and Clustal X version 2.0. Bioinformatics (Oxford, England) 2007; 23:2947-8; PMID:17846036; http://dx.doi.org/ 10.1093/bioinformatics/btm404 [DOI] [PubMed] [Google Scholar]
  • [41].Page RD. Visualizing phylogenetic trees using TreeView. Curr Protoc Bioinformatics 2002; Chapter 6:Unit 6.2; PMID:18792942 [DOI] [PubMed] [Google Scholar]
  • [42].Schutz P, Karlberg T, van den Berg S, Collins R, Lehtio L, Hogbom M, Holmberg-Schiavone L, Tempel W, Park HW, Hammarstrom M, et al.. Comparative structural analysis of human DEAD-box RNA helicases. PloS One 2010; 5:e12791; PMID:20941364; http://dx.doi.org/ 10.1371/journal.pone.0012791 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, Kiefer F, Cassarino TG, Bertoni M, Bordoli L, et al.. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 2014; 42:W252-8; PMID:24782522; http://dx.doi.org/ 10.1093/nar/gku340 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Schrodinger LLC. The PyMOL Molecular Graphics System. Version 1.3r1. 2010 [Google Scholar]
  • [45].Hwang W, Artan M, Seo M, Lee D, Nam HG, Lee SV. Inhibition of elongin C promotes longevity and protein homeostasis via HIF-1 in C. elegans. Aging cell 2015; 14:995-1002; PMID:26361075 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Kim YI, Bandyopadhyay J, Cho I, Lee J, Park DH, Cho JH. Nucleolar GTPase NOG-1 regulates development, fat storage, and longevity through insulin/IGF signaling in C. elegans. Mol Cell 2014; 37:51-7; PMID:24552710; http://dx.doi.org/ 10.14348/molcells.2014.2251 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Rual JF, Ceron J, Koreth J, Hao T, Nicot AS, Hirozane-Kishikawa T, Vandenhaute J, Orkin SH, Hill DE, van den Heuvel S, et al.. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res 2004; 14:2162-8; PMID:15489339; http://dx.doi.org/ 10.1101/gr.2505604 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Camacho C, Coulouris G, Avagyan V, Ma N, Papadopoulos J, Bealer K, Madden TL. BLAST+: architecture and applications. BMC Bioinformatics 2009; 10:421; PMID:20003500; http://dx.doi.org/ 10.1186/1471-2105-10-421 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Yang JS, Nam HJ, Seo M, Han SK, Choi Y, Nam HG, Lee SJ, Kim S. OASIS: online application for the survival analysis of lifespan assays performed in aging research. PloS One 2011; 6:e23525; PMID:21858155; http://dx.doi.org/ 10.1371/journal.pone.0023525 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Lee SJ, Hwang AB, Kenyon C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol 2010; 20:2131-6; PMID:21093262; http://dx.doi.org/ 10.1016/j.cub.2010.10.057 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Seo K, Choi E, Lee D, Jeong DE, Jang SK, Lee SJ. Heat shock factor 1 mediates the longevity conferred by inhibition of TOR and insulin/IGF-1 signaling pathways in C. elegans. Aging Cell 2013; 12:1073-81; PMID:23879233; http://dx.doi.org/ 10.1111/acel.12140 [DOI] [PubMed] [Google Scholar]
  • [52].Hwang AB, Ryu EA, Artan M, Chang HW, Kabir MH, Nam HJ, Lee D, Yang JS, Kim S, Mair WB, et al.. Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans. Proc Natl Acad Sci U S A 2014; 111:E4458-67; PMID:25288734; http://dx.doi.org/ 10.1073/pnas.1411199111 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1183845_Supplemental_Material.zip
kccy-15-14-1183845-s001.zip (216.9KB, zip)

Articles from Cell Cycle are provided here courtesy of Taylor & Francis

RESOURCES