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The Role of DND1 in Cancers

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The Role of DND1 in Cancers cancers Review The Role of DND1 in Cancers Yun Zhang *, Jyotsna D. Godavarthi , Abie Williams-Villalobo, Shahrazad Polk and Angabin Matin * Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA; [email protected] (J.D.G.); [email protected] (A.W.-V.); [email protected] (S.P.) * Correspondence: [email protected] (Y.Z.); [email protected] (A.M.); Tel.: +1-713-313-7557 (Y.Z.); +1-713-313-7160 (A.M.) Simple Summary: The Dead-End (DND1) protein can interact with different messenger RNAs (mRNAs) in the cell. It uses multiple mechanisms to regulate expression of proteins from their cognate mRNAs. High levels of DND1 are found in the progenitor cells that develop into the egg and sperm. Here we review how and why defects in DND1 cause tumors in the testes and ovaries of vertebrates. Unexpectedly, some recent reports indicate that DND1 may also participate in human cancer development in cells other than those of the testes and ovaries. The goal of this review is to summarize the literature on the role of DND1 in cancers to obtain perspective regarding future scientific endeavors on DND1 function. Abstract: The Ter mutation in Dead-End 1 (Dnd1), Dnd1Ter, which leads to a premature stop codon, has been determined to be the cause for primordial germ cell deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas in the 129/Sv-Ter mice. As an RNA-binding protein, DND1 can bind the 30-untranslated region (30-UTR) of mRNAs and 0 function in translational regulation. DND1 can block microRNA (miRNA) access to the 3 -UTR of target mRNAs, thus inhibiting miRNA-mediated mRNA degradation and up-regulating translation Citation: Zhang, Y.; Godavarthi, J.D.; or can also function to degrade or repress mRNAs. Other mechanisms of DND1 activity include Ter Williams-Villalobo, A.; Polk, S.; promoting translation initiation and modifying target protein activity. Although Dnd1 mutation Matin, A. The Role of DND1 in causes spontaneous TGCT only in male 129 mice, it can also cause ovarian teratomas in mice when Cancers. Cancers 2021, 13, 3679. combined with other genetic defects or cause germ cell teratomas in both genders in the WKY/Ztm https://doi.org/10.3390/ rat strain. Furthermore, studies on human cell lines, patient cancer tissues, and the use of human cancers13153679 cancer genome analysis indicate that DND1 may possess either tumor-suppressive or -promoting functions in a variety of somatic cancers. Here we review the involvement of DND1 in cancers, Academic Editor: David Wong including what appears to be its emerging role in somatic cancers. Received: 2 July 2021 Keywords: DND1; germ cell; teratomas; somatic cancers; translation regulator Accepted: 20 July 2021 Published: 22 July 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- The story of Dead-End 1 (DND1) in cancer of mouse germ cells can be traced back iations. almost half a century. A new spontaneously arising mutation led to generation of the new inbred subline of mice (129/Sv-Ter) that exhibited primordial germ cell (PGC) deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas [1–3]. These recessive phenotypes mapped to mouse chromosome 18, or the Ter locus [4,5]. In 2005, twenty years after the 129/Sv-Ter mouse line was isolated, positional Copyright: © 2021 by the authors. Ter Dead-End Licensee MDPI, Basel, Switzerland. cloning of identified the genetic defect to a mutation in 1, a mouse ortholog This article is an open access article of the zebrafish dead-end gene required for PGC migration and survival [6]. Mouse Dnd1 distributed under the terms and contains four exons. Ter is due to a single nucleotide substitution occurring spontaneously conditions of the Creative Commons in exon 3 of Dnd1, which transforms the arginine residue at amino acid (aa) 190 into a Attribution (CC BY) license (https:// premature stop codon, thus causing either truncation or loss of DND1 expression (Figure1) . creativecommons.org/licenses/by/ This mutation results in the phenotypes of PGC loss, male and female sterility, and the 4.0/). high incidence of TGCT in males of the 129/Sv mice. Cancers 2021, 13, 3679. https://doi.org/10.3390/cancers13153679 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 12 Cancers 2021, 13, 3679 1). This mutation results in the phenotypes of PGC loss, male and female sterility, and2 ofthe 12 high incidence of TGCT in males of the 129/Sv mice. FigureFigure 1. 1. SchematicSchematic representation representation of of the the structure structure of of mouse, mouse, rat, rat, and and human human DND1 DND1 proteins. proteins. The The RNARNA recognition recognition motif motif 1 1 (RRM1), (RRM1), RNA RNA recognitio recognitionn motif motif 2 2 (RRM2) (RRM2) and and double double stranded stranded RNA- RNA- bindingbinding motif motif (DSRM (DSRM)) are are shown. shown. TerTer mutationmutation transforms transforms arginine arginine at amino amino acid acid (aa) (aa) 190 190 in in mouse mouse andand tryptophan tryptophan at at aa aa 289 289 in in rat rat DND1 DND1 into into a a prem prematureature stop stop codon. codon. The The re redd bar bar in in RRM2 RRM2 represents represents thethe HRAAAMA HRAAAMA motif motif spanning spanning from from aa aa 189 189 to to 195 195 in in all all three three species. species. Th Thee predicated predicated mouse mouse and and Ter ratrat DND1 DND1Ter proteinprotein are are also also shown shown underneath underneath the the wild-type wild-type (WT) (WT) protein, protein, respectively. respectively. Please Please note that whether DND1Ter causes truncation or loss of DND1 expression is still controversial. The note that whether DND1Ter causes truncation or loss of DND1 expression is still controversial. The NCBI Reference Sequence numbers for mouse, rat and human DND1 proteins are NP_775559.2, NCBI Reference Sequence numbers for mouse, rat and human DND1 proteins are NP_775559.2, NP_001102849.1 and NP_919225.1, respectively, accessed on 20 July 2021. NP_001102849.1 and NP_919225.1, respectively, accessed on 20 July 2021. DND1 is an RNA-binding protein that contains two RNA recognition motifs (RRMs) DND1 is an RNA-binding protein that contains two RNA recognition motifs (RRMs) inin tandem, tandem, spanningspanning approximatelyapproximately aa aa residues residues 58–136 58–136 and and 138–218 138–218 (https://www.uniprot. (https://www.uni- prot.org/uniprot/Q6VY05,org/uniprot/Q6VY05, accessed accessed on on 18 18 July July 2021), 2021), respectively,respectively, followedfollowed byby a a double double strandedstranded RNA-binding RNA-binding motif motif at at the the carboxyl carboxyl (C)-terminus (C)-terminus (Figure (Figure 1).1 The). The amino amino (N)-ter- (N)- minalterminal RRM1 RRM1 is canonical is canonical and andessential essential for binding for binding specific specific mRNAs mRNAs [7,8]. [ 7The,8]. RRM2 The RRM2 is less is conservedless conserved and contains and contains the HRAAAMA the HRAAAMA motif motif(Figure (Figure 1, described1, described below). below). Over the Over years, the DND1years, DND1has been has found been foundto possess to possess diverse diverse molecular molecular functions. functions. The most The moststudied studied is its isrole its inrole translation in translation regulation regulation [7–10]. [7 –In10 addition]. In addition to TGCTs, to TGCTs, DND1 DND1 has also has alsobeen been shown shown to po- to tentiallypotentially impact impact ovarian ovarian teratomas teratomas (OTs) (OTs) and and somatic somatic tumors tumors [11–19]. [11–19]. Because Because DND1 DND1 has has beenbeen described described as aa proteinprotein primarilyprimarily expressed expressed in in germ germ cells, cells, the the multiple multiple research research reports re- portsand databaseand database evidence evidence of DND1 of DND1 involvement involvement in somatic in somatic cancers cancers are unexpected. are unexpected. Here we Herereview we studies review that studies have that investigated have investigated mechanisms mechanisms of DND1 of function DND1 infunction vertebrates in verte- and bratesespecially and itsespecially role in somatic its role cancers,in somatic including cancers, human including cancers. human A PubMed cancers. searchA PubMed using search“DND1” using as the “DND1” keyword as wasthe conducted,keyword was which conducted, returned which 121 results returned as of 121 June results 2021. Theseas of June121 papers2021. These were 121 manually papers screenedwere manually to identify screened those to that identify are related those tothat the are topic related of this to thepresent topicreview. of this present review. 2. Molecular Mechanisms of DND1 Function 2.1. mRNA Stabilization Several studies have demonstrated that DND1 can bind specific mRNAs and block microRNA (miRNA) access from the 30-untranslated region (30-UTR) of target mRNAs and inhibit miRNA-mediated mRNA degradation, thus up-regulating translation (Figure2a). Cancers 2021, 13, x FOR PEER REVIEW 3 of 12 2. Molecular Mechanisms of DND1 Function 2.1. mRNA Stabilization Cancers 2021, 13, 3679 Several studies have demonstrated that DND1 can bind specific mRNAs and block3 of 12 microRNA (miRNA) access from the 3′-untranslated region (3′-UTR) of target mRNAs and inhibit miRNA-mediated mRNA degradation, thus up-regulating translation (Figure 2a). The target mRNAs of DND1 that have been studied are often those involved in regu- The target mRNAs of DND1 that have been studied are often those involved in regulation lation of the cell cycle or apoptosis. For example, DND1 binds to 0the 3′-UTR of p27 mRNA andof the blocks cell cycle miR-221 or apoptosis. so as to up-regulate For example, p27 DND1 protein binds expression to the 3 -UTR[7].
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