cancers Review Role of PUM RNA-Binding Proteins in Cancer Maciej J. Smialek * , Erkut Ilaslan , Marcin P. Sajek and Jadwiga Jaruzelska * Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland; [email protected] (E.I.); [email protected] (M.P.S.) * Correspondence: [email protected] (M.J.S.); [email protected] (J.J.) Simple Summary: PUM1 and PUM2 are RNA-binding Pumilio proteins controlling the accessibility of hundreds of mRNAs for translation in a variety of human tissues. As a result, PUMs exemplify one of the mechanisms safeguarding the cellular proteome. PUM expression is disturbed in can- cer, resulting in dysregulation of their target mRNAs. These targets encode factors responsible for processes usually affected in cancer, such as proliferation, apoptosis, and the cell cycle. This review describes PUM1 and PUM2 ribonucleoprotein networks and highlights the mechanisms underlying the regulatory role of PUM proteins and, most importantly, the emerging impact of PUM dysregulation in cancer. It also emphasizes the importance of upcoming studies on PUM proteins in the context of cancer, as they may provide new therapeutic targets in the future. Abstract: Until recently, post-transcriptional gene regulation (PTGR), in contrast to transcriptional regulation, was not extensively explored in cancer, even though it seems to be highly important. PUM proteins are well described in the PTGR of several organisms and contain the PUF RNA-binding domain that recognizes the UGUANAUA motif, located mostly in the 30 untranslated region (30UTR) of target mRNAs. Depending on the protein cofactors recruited by PUM proteins, target mRNAs are directed towards translation, repression, activation, degradation, or specific localization. Abnormal profiles of PUM expression have been shown in several types of cancer, in some of them being different for PUM1 and PUM2. This review summarizes the dysregulation of PUM1 and PUM2 expression in several cancer tissues. It also describes the regulatory mechanisms behind the activity Citation: Smialek, M.J.; Ilaslan, E.; of PUMs, including cooperation with microRNA and non-coding RNA machineries, as well as the Sajek, M.P.; Jaruzelska, J. Role of PUM alternative polyadenylation pathway. It also emphasizes the importance of future studies to gain RNA-Binding Proteins in Cancer. a more complete picture of the role of PUM proteins in different types of cancer. Such studies may Cancers 2021 13 , , 129. result in identification of novel targets for future cancer therapies. https://doi.org/10.3390/cancers13 010129 Keywords: cancer; mRNA; PUM proteins; post-transcriptional gene regulation; PTGR; 30 untrans- lated regions; 30UTR Received: 5 November 2020 Accepted: 31 December 2020 Published: 3 January 2021 Publisher’s Note: MDPI stays neu- 1. Introduction tral with regard to jurisdictional clai- A large body of knowledge regarding genetic mutations and associated transcriptional ms in published maps and institutio- dysregulation, which is critical for carcinogenesis, has been accumulated in recent decades. nal affiliations. Although growing evidence indicates that dysregulation of post-transcriptional gene ex- pression plays a highly important role in cancer as well, with the exception of microRNAs this role has been neglected. Post-transcriptional gene expression regulation (PTGR) mainly encompasses RNA processing, which takes place beyond transcription, starting in the nu- Copyright: © 2021 by the authors. Li- cleus and continuing in the cytoplasm [1]. The main nuclear RNA processing steps consist censee MDPI, Basel, Switzerland. 0 0 This article is an open access article of 7-methylguanosine cap synthesis on the 5 -end of pre-mRNA, generation of the 3 -end distributed under the terms and con- by cleavage and polyadenylation, including alternative polyadenylation (APA), and a mul- ditions of the Creative Commons At- tistep splicing reaction that removes introns and produces mature mRNA molecules. These tribution (CC BY) license (https:// nuclear RNA processing events are mediated by a multitude of RNA-binding proteins 0 creativecommons.org/licenses/by/ (RBPs) that associate with the nascent mRNA as soon as the 5 -end is transcribed via RNA 4.0/). polymerase II catalysis [2]. As is now well-known, a variety of RBPs are dysregulated in Cancers 2021, 13, 129. https://doi.org/10.3390/cancers13010129 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 13 Cancers 2021, 13, 129 2 of 13 is transcribed via RNA polymerase II catalysis [2]. As is now well-known, a variety of differentRBPs are cancerdysregulated types (for in adifferent review, seecancer [3]). types This review(for a review, focuses see on [3] Pumilio). This proteins, review foc PUM1uses andon Pumilio PUM2, proteins, which represent PUM1 and well-described PUM2, which examples represent of well RBPs-described playing examples a role in PTGR of RBPs in metazoans,playing a role including in PTGR humans in metazoans, (for a review, including see [humans4]), as well (for as a inreview, plants see [5]. [4] There), as iswell accu- as mulatingin plants evidence[5]. There now is accumulating that expression evidence of PUM proteinsnow that is expression dysregulated of inPUM several prot cancerseins is (fordysregulated a review, seein several [4]). PUM cancers proteins (for a contain review, a see C-terminal [4]). PUM highly proteins conserved contain PUFa C-terminal domain thathighly binds conserved to mRNA PUF molecules. domain that This binds domain to mRNA consists molecules. of eight imperfect This domain tandem consists repeats of ofeight 36 aminoimperfect acids tandem (aa) (Figure repeats1). of These 36 amino repeats acids form (aa a) curved(Figure structure,1). These eachrepeats of whichform a iscurved in contact structure, with each one of base which within is in a contact PUM-binding with one element base within (PBE)—an a PUM- eight-nucleotidebinding element conserved(PBE)—an motifeight-nucleotide UGUAHAUW, conserved located motif mostly UGUAHAUW, in the 30 untranslated located mostly region in (3 the0UTR) 3′ un- of targettranslated mRNAs region (Figure (3′UTR1)[)6 of–9 target]. mRNAs (Figure 1) [6–9]. Figure 1. Models of human PUF1 and PUF2 RNA RNA-binding-binding domain crystal structure in complex with PUM PUM-binding-binding element (PBE)(PBE) ofof p38p38αα mRNAmRNA target.target. Left panel—cartoonpanel—cartoon model of PUF1 structure in a complexcomplex with PBEPBE ofof p38p38αα mRNAmRNA (PDB(PDB id:3Q0M);id:3Q0M); middlemiddle panel—cartoonpanel—cartoon model of PUF2PUF2 structure in a complexcomplex withwith PBEPBE ofof p38p38αα mRNAmRNA (PDB(PDB id:3Q0R);id:3Q0R); rightright panel—overlaypanel—overlay of tube models of PUF1 (blue)(blue) andand PUF2PUF2 (yellow)(yellow) structuresstructures in complexcomplex withwith PBEPBE ofof p38p38αα mRNA.mRNA. TheThe overlay panelpanel shows a more open PUF1 compared to the PUF2-domain,PUF2-domain, bindingbinding thethe same PBE of p38p38αα mRNA. Visualized models werewere obtainedobtained using using BioRender.com BioRender.com from from 3Q0M 3Q0M and and 3Q0R 3Q0R PDB PDB structures structures [10]. [10]. PUF—PUM PUF—PUM RNA-binding RNA-binding domain; do- main; PBE—PUM binding element UGUAHAUW; PDB—Protein Database Bank. PBE—PUM binding element UGUAHAUW; PDB—Protein Database Bank. While the original Drosophila melanogaster PUM proteinprotein is unique, there areare severalseveral Pum proteins that exist in yeast, Caenorhabditis elegans,, andand otherother modelmodel organisms.organisms. ThereThere are two PUM genes in humans on chromosomes 1 and 2 called PUM1 and PUM2,, respec- tively, and they they encode encode PUM1 PUM1 and and PUM2 PUM2 proteins, proteins, respe respectivelyctively (for (for a review, a review, see [4] see). [The4]). Therate rateof the of overall the overall aa similarity aa similarity between between PUM1 PUM1 and PUM2 and PUM2 protein protein is 83%, is 83%,with the with PUF the- PUF-domaindomain being being 91% 91%identical identical [10]. [10 PUMs]. PUMs bind bind to todifferent different protein protein cofactors, cofactors, such such asas NANOS [[11],11], DAZ-likeDAZ-like(DAZL) (DAZL) [ 12[12],], and and DEAD-Box DEAD-Box Helicase Helicase 20 20 (DDX20) (DDX20 [13) [13].]. Binding Binding of PUMof PUM proteins proteins with with their their co-factors co-factors in in most most cases cases directs directsa a givengiven mRNAmRNA towards repres- sion, leading mostly to degradation.degradation. This binding, however, may also stabilize mRNA, activate translation, and/or and/or storage storage in in specific specific subcellular subcellular compartments compartments (F (Figureigure 22) )(for (for a areview, review, see see [4] [)4. ]).It has It has been been demonstrated demonstrated that that mRNA mRNA repression repression by PUM by PUM proteins proteins con- consistssists of the of thepromotion promotion of ofdeadenylation deadenylation [14 [14–16–16], ],and and in in some some cases cases,, also also decapping decapping [17]. [17]. Deadenylation is followed mostlymostly byby degradationdegradation [[18,19],18,19], whichwhich isis inin lineline withwith thethe findingfinding that the presence of PBEs is closely associated with lower mRNA stability [20–22]. This phenomenon was confirmed by studies in several human cell lines, such as U2OS, HEK293, Cancers 2021, 13, x FOR PEER REVIEW 3 of 13 Cancers 2021, 13, 129 3 of 13 that the presence of PBEs is closely associated