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When DNA Meets RNA

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When DNA Meets RNA cells Review The Ultimate (Mis)match: When DNA Meets RNA Benoit Palancade 1,* and Rodney Rothstein 2,* 1 Institut Jacques Monod, Université de Paris, CNRS, F-75006 Paris, France 2 Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY 10032, USA * Correspondence: benoit.palancade@ijm.fr (B.P.); rjr4@cumc.columbia.edu (R.R.) Abstract: RNA-containing structures, including ribonucleotide insertions, DNA:RNA hybrids and R-loops, have recently emerged as critical players in the maintenance of genome integrity. Strikingly, different enzymatic activities classically involved in genome maintenance contribute to their gen- eration, their processing into genotoxic or repair intermediates, or their removal. Here we review how this substrate promiscuity can account for the detrimental and beneficial impacts of RNA in- sertions during genome metabolism. We summarize how in vivo and in vitro experiments support the contribution of DNA polymerases and homologous recombination proteins in the formation of RNA-containing structures, and we discuss the role of DNA repair enzymes in their removal. The diversity of pathways that are thus affected by RNA insertions likely reflects the ancestral function of RNA molecules in genome maintenance and transmission. Keywords: DNA repair; genetic recombination; genetic stability; transcription; RNA; ribonucleotide; DNA:RNA hybrid; R-loop 1. Introduction Citation: Palancade, B.; Rothstein, R. The Ultimate (Mis)match: When Among the many scientific contributions that Miro Radman has made to our under- DNA Meets RNA. Cells 2021, 10, 1433. standing of genome biology, his work on the SOS response and mismatch repair stands https://doi.org/10.3390/cells10061433 out amongst the most visionary. Combining observations that he and his colleagues made using bacteria and their phages, he outlined the main features of the cellular response to Academic Editors: Bernard S. Lopez DNA damage and foreshadowed its importance for genetic stability [1–4]. An important and Ivan Matic concept arising from these pioneering studies is that damage to the genome can be tolerated by calling into play the cellular machineries that ensure viability, even at the expense of Received: 12 May 2021 genetic integrity. Accepted: 5 June 2021 During the past several years, an increasing number of obstacles to DNA-related Published: 8 June 2021 transactions was found to similarly trigger DNA repair and tolerance mechanisms. Among them, RNA-containing structures have recently caught the attention of DNA biologists, as Publisher’s Note: MDPI stays neutral addressed in several recent excellent reviews [5–10]. These range from single ribonucleotide with regard to jurisdictional claims in insertions to RNA stretches, DNA:RNA hybrids and R-loops, in which a single-stranded published maps and institutional affil- DNA is displaced (Figure1). Such structures are observed in diverse species and represent iations. a significant fraction of their genomes: for example, ribonucleotides are incorporated in newly synthesized DNA at an overall rate of ~1:1000 nucleotides [11] and R-loops occupy approximately 5% of the human genome [12]. It has become increasingly clear that these structures are relevant for genome integrity: on the one hand, genetic screens have high- Copyright: © 2021 by the authors. lighted the importance of RNA metabolism factors in the DNA damage response [13–16], Licensee MDPI, Basel, Switzerland. and on the other hand, factors classically associated with DNA repair or genome main- This article is an open access article tenance handle RNA-containing substrates in vitro [17–20]. Finally, dedicated enzymes distributed under the terms and can specifically process DNA/RNA hybrid structures, as exemplified by the H class of conditions of the Creative Commons nucleases (RNase H1 and H2 in eukaryotes), which hydrolyze RNA moieties in DNA:RNA Attribution (CC BY) license (https:// duplexes [21]. creativecommons.org/licenses/by/ 4.0/). Cells 2021, 10, 1433. https://doi.org/10.3390/cells10061433 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 16 Here, we review evidence obtained from in vivo studies in light of findings arising from in vitro experiments and summarize: (i) how cellular enzymes involved in DNA me- tabolism recognize, utilize or tolerate RNA-containing substrates, and (ii) how this sub- Cells 2021, 10, 1433 strate promiscuity can either trigger the generation of genotoxic structures, or impact 2their of 16 repair. FigureFigure 1. TheThe variety variety of RNA-containing struct structuresures in the genome. Different Different types of ribonucleotide- or RNA-containing structuresstructures are are represented in orange. The The enzymes enzymes with with reported reported contributions contributions to to th theireir generation generation or or removal removal are are listed listed in in blueblue and and magenta, respectively, respectively, and the repair pathways with which they are associated ar aree italicized. The The orange and greygrey arrows arrows indicate indicate the the direction direction of of RNA RNA and and DNA DNA synthesis, synthesis, respectively. respectively. RNAP, RNAP, RNA polymerase. ( (aa),), Ribonucleotide Ribonucleotide incorporationincorporation during during DNA DNA replication. replication. For For simplicity, simplicity, only only one one branch branch of of the the replication replication fork fork is is represented. represented. ( (bb),), R-loop R-loop formationformation and and resolution. resolution. (c (),c ),DNA:RNA DNA:RNA hybrid hybrid accumulation accumulation at DSBs. at DSBs. (d), (RNA-templatedd), RNA-templated DNA DNA repair. repair. The cDNA The cDNA pro- duced upon reverse-transcription can also be used in homology-directed repair in a Rad51- and Rad52-dependent process produced upon reverse-transcription can also be used in homology-directed repair in a Rad51- and Rad52-dependent (not depicted). See text for details. process (not depicted). See text for details. 2. WhenHere, DNA we reviewPolymerases evidence Meet obtained Ribonucleotides from in vivo studies in light of findings arising 2.1.from DNAin vitro Polymerasesexperiments Can Use and rNTPs summarize: during DNA (i) how Synthesis cellular enzymes involved in DNA metabolismSince DNA recognize, polymerases utilize are or generally tolerate RNA-containingunable to catalyze substrates, de novo DNA and synthesis, (ii) how thisthe initiationsubstrate of promiscuity DNA replication can either requires trigger the the activity generation of DNA-dependent of genotoxic structures, RNA polymerases, or impact ortheir primases, repair. which utilize ribonucleotides triphosphate (rNTPs) to synthesize short, ~10 nt-long RNA primers, providing a free 3′ hydroxyl for further leading and lagging strand 2. When DNA Polymerases Meet Ribonucleotides elongation. Notably, replicative DNA polymerases (Pol α, Pol δ, and Pol ε), despite having 2.1. DNA Polymerases Can Use rNTPs during DNA Synthesis a steric-gate residue favoring dNTP selection at their nucleotide binding pocket, can also incorporateSince DNA rNMPs polymerases into newly are synthesized generally unableDNA, as to highlighted catalyze de novoby inDNA vitro synthesis,studies ([11]; the Figureinitiation 1a). of Even DNA with replication rNMP incorporation requires the activity disfavored, of DNA-dependent the high cellular RNA concentration polymerases, of rNTPsor primases, compared which to utilizedNTPs ribonucleotides results in rates triphosphateof ribonucleotide (rNTPs) misincorporation to synthesize short, within ~10 nas- nt- 0 centlong DNA RNA from primers, ~1:600 providing to ~1:5000 a freedepending 3 hydroxyl on the for DNA further polymerase leading andconsidered lagging [11,22]. strand Thus,elongation. rNMP Notably, insertion replicative represents DNA a major polymerases error that (Poloccursα, Polduringδ, and DNA Pol replication,"), despite havingwhich hasa steric-gate been confirmed residue by favoring genome-wide dNTP selection mapping at [23]. their nucleotide binding pocket, can also incorporate rNMPs into newly synthesized DNA, as highlighted by in vitro studies ([11]; Figure1a). Even with rNMP incorporation disfavored, the high cellular concentration of rNTPs compared to dNTPs results in rates of ribonucleotide misincorporation within nascent DNA from ~1:600 to ~1:5000 depending on the DNA polymerase considered [11,22]. Thus, rNMP insertion represents a major error that occurs during DNA replication, which has been confirmed by genome-wide mapping [23]. Cells 2021, 10, 1433 3 of 16 2.2. Recognition of Embedded Ribonucleotides: Genotoxicity vs. Tolerance The insertion of rNMPs in the genome enhances DNA reactivity, favors alkali cleavage, and causes backbone distortions, with possible repercussions on DNA-related transactions, such as replication and chromatin assembly [24]. In view of their potentially deleterious effects, genome-embedded rNMPs are efficiently removed by ribonucleotide excision repair (RER), an error-free pathway that relies on ribonucleotide recognition and excision by RNase H2, which also removes the RNA stretches generated by primase activity [24]. Alternatively, in the absence of RNase H2, ribonucleotide insertion leads to topoisomerase I-dependent cleavage, eventually leading to short deletions in repeated sequences, as revealed by in vitro and in vivo studies [25,26]. Furthermore, the accumulation of rNMPs insertions in the genome causes replication stress and genetic instability, as shown by
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