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The Genome Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer

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The Genome Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer G C A T T A C G G C A T genes Review The Genome Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer Mohammad Mahtab 1,2 , Ana Boavida 1 , Diana Santos 1 and Francesca M. Pisani 1,* 1 Istituto di Biochimica e Biologia Cellulare—CNR, Via P. Castellino, 111, 80131 Naples, Italy; [email protected] (M.M.); [email protected] (A.B.); [email protected] (D.S.) 2 Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Università degli Studi della Campania Luigi Vanvitelli, Via Vivaldi, 43, 81100 Caserta, Italy * Correspondence: [email protected]; Tel.: +39-0816132292 Abstract: DDX11/ChlR1 is a super-family two iron–sulfur cluster containing DNA helicase with roles in DNA replication and sister chromatid cohesion establishment, and general chromosome architecture. Bi-allelic mutations of the DDX11 gene cause a rare hereditary disease, named War- saw breakage syndrome, characterized by a complex spectrum of clinical manifestations (pre- and post-natal growth defects, microcephaly, intellectual disability, heart anomalies and sister chromatid cohesion loss at cellular level) in accordance with the multifaceted, not yet fully understood, physio- logical functions of this DNA helicase. In the last few years, a possible role of DDX11 in the onset and progression of many cancers is emerging. Herein we summarize the results of recent studies, carried out either in tumoral cell lines or in xenograft cancer mouse models, suggesting that DDX11 may have an oncogenic role. The potential of DDX11 DNA helicase as a pharmacological target for novel anti-cancer therapeutic interventions, as inferred from these latest developments, is also discussed. Citation: Mahtab, M.; Boavida, A.; Keywords: DDX11/ChlR1; genome stability; sister chromatid cohesion; DNA helicase; long noncod- Santos, D.; Pisani, F.M. The Genome ing RNAs; human papillomavirus; cancer; oncogene; tumor suppressor gene Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer. Genes 2021, 12, 395. https://doi.org/ 10.3390/genes12030395 1. Introduction DNA helicases are enzymes able to unwind DNA duplexes and translocate along nu- Academic Editor: Martin Kupiec cleic acid strands with a specific directionality (30 to 50 or vice versa) by utilizing the energy derived from nucleoside triphosphate hydrolysis (typically ATP) [1,2]. Human genome Received: 22 February 2021 codes for at least 31 different DNA helicases are classified into two major (superfamily Accepted: 8 March 2021 1 and 2) and four minor groups based on their sequence similarity. They are ubiquitous Published: 10 March 2021 enzymes, found in all kingdoms of life, including bacteriophages and DNA eukaryotic viruses. DNA helicases display different reaction requirements and substrate specificity, Publisher’s Note: MDPI stays neutral being able to melt not only B-form DNA duplex molecules, but also nonconventional DNA with regard to jurisdictional claims in published maps and institutional affil- structures such as G-quadruplexes and triplexes, displacement loops, Holliday junctions, iations. stem-loops, and cruciform structures. Moreover, some DNA helicases are able to actively displace DNA-bound proteins. DNA helicases play key functions in a variety of DNA replication/repair/recombination pathways that are important for genome stability main- tenance. It is, therefore, not surprising that mutations and/or dysregulated expressions of DNA helicase encoding genes are linked to many hereditary diseases, neurodegenerative Copyright: © 2021 by the authors. disorders, and cancers [3]. However, in several instances, the molecular mechanisms Licensee MDPI, Basel, Switzerland. underlying the related clinical phenotypes are not fully understood. This article is an open access article distributed under the terms and The role played by DNA helicases in cancer is complex and depends on the genetic conditions of the Creative Commons context and the tumor type. In fact, inactivating mutations of DNA helicase genes can Attribution (CC BY) license (https:// predispose to cancer, suggesting a tumor suppressor function for some of these enzymes. creativecommons.org/licenses/by/ Conversely, the level of expression of many DNA helicases is enhanced in pre-cancerous 4.0/). Genes 2021, 12, 395. https://doi.org/10.3390/genes12030395 https://www.mdpi.com/journal/genes GenesGenes2021 202112, 12, x FOR PEER REVIEW 2 of 15 , , 395 2 of 15 andindividual cancerous, indicating cells and tissuesa pro-tumorigenic compared to behavior the healthy of the counterparts corresponding of the enzymes. same individ- In this ual,regard, indicating it is well a pro-tumorigenic established that behavior certain of DNA the corresponding helicases may enzymes. help highly In this proliferating regard, it iscancer well established cells to counteract that certain the DNA replication helicases stress may deriving help highly from proliferating the conflicts cancer between cells the toreplication counteract and the replicationtranscription stress machineries deriving, from and theto conflictsrepair DNA between lesions the due replication to either andendogenous transcription or exogenous machineries, insults and [4 to–6 repair]. DNA lesions due to either endogenous or exogenousIn this insults review, [4– 6we]. summarize what is known about a potential function in cancer of humanIn this DDX11, review, a DNA we summarize helicase, involved what is knownin various about genome a potential maintenance function pathways in cancer and ofin human sister chromatid DDX11, a DNAcohesion helicase, establishment. involved inWe various start by genome providing maintenance a general pathways overview of andthe inmolecular sister chromatid and cellular cohesion roles establishment. of DDX11; then, We start we bydescribe providing the aregulation general overview of DDX11 ofactivity the molecular by the long and noncoding cellular roles RNA of DDX11; named CO then,NCR we and describe the mechanism the regulation by which of DDX11 DDX11 activitypromotes by thehuman long noncodingpapillomavirus RNA genome named CONCR replicationand and the mechanismmaintenance; by whicha final DDX11section is promotesdedicated human to the papillomavirusrole DDX11 is believed genome to replication play in various and maintenance; cancer types a. final section is dedicated to the role DDX11 is believed to play in various cancer types. 2. Molecular Properties of DDX11 2. Molecular Properties of DDX11 DDX11/ChlR1 (Chl1 in yeast) belongs to the group of super-family 2 (SF2) DNA DDX11/ChlR1 (Chl1 in yeast) belongs to the group of super-family 2 (SF2) DNA helicases characterized by the presence of an iron–sulfur cluster (Fe–S) domain [7–9]. This helicases characterized by the presence of an iron–sulfur cluster (Fe–S) domain [7–9]. This subclass also includes the Xeroderma pigmentosum group D (XPD) protein, FANCJ, and subclass also includes the Xeroderma pigmentosum group D (XPD) protein, FANCJ, and RTEL1RTEL1 (see (see Figure Figure1). 1) All. All these these DNA DNA helicases helicases are are genetically genetically linked linked to rareto rare hereditary hereditary diseasesdiseases that that display display genome genome instability instability features features and, in and, some in cases, some also cases, cancer also suscepti- cancer bility.susceptibility. Bi-allelic mutations Bi-allelic mutations of the DDX11 of thegene DDX11 cause Warsawgene cause breakage Warsaw syndrome breakage (WABS), syndrome a rare(WAB pathologyS), a rare that pathology is characterized that is bycharacterized a complex spectrum by a complex of symptoms spectrum including of symptoms pre- andincluding post-natal pre growth- and post defects,-natal microcephaly, growth defects, various microcephaly, degree of intellectualvarious degree disability, of intellectual heart defects,disability, and heart at cytological defects, and level at sister cytological chromatid level cohesion sister chromatid abnormalities, cohesion giving abnormalit rise to anies, alteredgiving chromosome rise to an altered morphology chromosome [10]. The chromosomalmorphology cohesion[10]. The anomalies chromosomal observed cohesion in fibroblastsanomalies or observed lymphoblasts in fibroblasts derived or from lymphoblasts WABS patients derived or other from DDX11-deficient WABS patients or cells other consistDDX11 of-deficient a premature cells centromere consist of a division premature (PCD), centromere characterized division by a (PCD), loosened characterized centromere by constriction,a loosened likely centromere due to repulsion constriction, of the correspondinglikely due to heterochromaticrepulsion of the regions; corresponding besides, inheterochromatic an appreciable numberregions; ofbesides, metaphase in an chromosome appreciable spreadsnumber ofof the metaphase above cell chromosome lines, all thespreads sister chromatidof the above pairs cell appear lines, all completely the sister separated,chromatid apairs condition appear defined completely as premature separated, chromatida condition separation defined as (PCS) premature [11]. chromatid separation (PCS) [11]. Q I Ia Fe-S II Arch III IV V VI XPD 760 Q I T Ia Fe-S II Arch III IV V VI DDX11 906 Q I Ia Fe-S II Arch III IV V VI FANCJ 1249 Q I Ia Fe-S II Arch III IV V VI RTEL1 1300 FigureFigure 1. 1.A A schematic schematic representation representation of of the the polypeptide polypeptide chain chain of of human human super-family super-family 2 DNA 2 DNA helicaseshelicases containing containing an an Fe–S Fe– clusterS cluster is reported.is
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