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R-loop
open-in-new
<h2 id="history">History</h2> <p> R-looping was first described in 1976.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> Independent R-looping studies from the laboratories of <a href="/facts/Richard_J._Roberts/j3ugQAcJ">Richard J. Roberts</a> and <a href="/facts/Phillip_A._Sharp/uMH3Q4wx">Phillip A. Sharp</a> showed that <a href="/facts/Protein/Jxmagu3E">protein</a> coding <a href="/facts/Adenovirus/JLX5IKHt">adenovirus</a> <a href="/facts/Gene/e1swwPY6">genes</a> contained DNA sequences that were not present in the mature mRNA.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a><a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> Roberts and Sharp were awarded the <a href="/facts/Nobel_Prize_in_Physiology_or_Medicine/rlnpJX84">Nobel Prize</a> in 1993 for independently discovering introns. After their discovery in adenovirus, introns were found in a number of <a href="/facts/Eukaryote/SkwyPLMA">eukaryotic</a> genes such as the eukaryotic <a href="/facts/Ovalbumin/0b3aU87B">ovalbumin</a> gene (first by the O'Malley laboratory, then confirmed by other groups),<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> <a href="/facts/Hexon_protein/AD2qotq2">hexon</a> DNA,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> and <a href="/facts/Extrachromosomal_DNA/SKgfpl5s">extrachromosomal</a> <a href="/facts/RRNA/zy5FxddY">rRNA</a> genes of <i><a href="/facts/Tetrahymena_thermophila/jo72mbCS">Tetrahymena thermophila</a></i>.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p><p>In the mid-1980s, development of an <a href="/facts/Antibody/MX8pdTdP">antibody</a> that binds specifically to the R-loop structure opened the door for <a href="/facts/Immunofluorescence/lBrwxaYI">immunofluorescence</a> studies, as well as genome-wide characterization of R-loop formation by <a href="/facts/DRIP-seq/mtPr1SFt">DRIP-seq</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h2 id="r-loop-mapping">R-loop mapping</h2> <p>R-loop mapping is a laboratory technique used to distinguish introns from <a href="/facts/Exon/8KWJtLuN">exons</a> in double-stranded DNA.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> These R-loops are visualized by <a href="/facts/Electron_microscopy/XtaBktwF">electron microscopy</a> and reveal intron regions of DNA by creating unbound loops at these regions.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h2 id="r-loops-in-vivo">R-loops <i>in vivo</i></h2> <p>The potential for R-loops to serve as replication primers was demonstrated in 1980.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> In 1994, R-loops were demonstrated to be present <i>in vivo</i> through analysis of plasmids isolated from <i><a href="/facts/Escherichia_coli/nR4Gvl56">E. coli</a></i> mutants carrying mutations in <a href="/facts/Topoisomerase/CceQ9b1Y">topoisomerase</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> This discovery of <a href="/facts/Endogeny_(biology)/DFkSLkRI">endogenous</a> R-loops, in conjunction with rapid advances in genetic <a href="/facts/Sequencing/ncpzobwG">sequencing</a> technologies, inspired a blossoming of R-loop research in the early 2000s that continues to this day.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h3>Regulation of R-loop formation and resolution</h3> <p>More than 50 proteins that appear to influence R-loop accumulation, and while many of them are believed to contribute by sequestering or processing newly transcribed RNA to prevent re-annealing to the template, mechanisms of R-loop interaction for many of these proteins remain to be determined.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p><p>There are three main classes of enzyme that can remove RNA that becomes trapped in the duplex within an R-loop. <a href="/facts/Ribonuclease_H/UKaLv8fh">RNaseH</a> enzymes are the primary proteins responsible for the dissolution of R-loops, acting to degrade the RNA moiety in order to allow the two complementary DNA strands to anneal.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Alternatively, <a href="/facts/Helicase/IemubWzR">Helicases</a> act to unwind the RNA:DNA duplex so that RNA is released. <a href="/facts/SETX/qd7dtmFc">Senataxin</a> is one helicase that can move along ssRNA, and appears to be necessary for preventing R-loop formation at transcription pause sites.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> The third enzyme class capable of removing R-loops are branchpoint translocases such as <a href="/facts/FANCM/cyDXhqwh">FANCM</a>, <a href="/facts/SMARCAL1/YReLUFfy">SMARCAL1</a> and ZRANB3 in humans or RecG in bacteria.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> Branchpoint translocases act on the double-stranded DNA adjacent to the DNA:RNA hybrid. By pushing at the branchpoint, they act to "zip up" the DNA and expel the trapped RNA. This makes branchpoint translocases efficient at removing both RNA and proteins that are bound to the R-loop structure. Branchpoint translocases may work together with RNaseH and helicases on some types of R-loops that occur at challenging structures. </p> <h3>Roles of R-loops in genetic regulation</h3> <p>R-loop formation is a key step in <a href="/facts/Immunoglobulin_class_switching/q8w8PWoY">immunoglobulin class switching</a>, a process that allows activated <a href="/facts/B_cell/6Y1tgwwp">B cells</a> to modulate <a href="/facts/Antibody/MX8pdTdP">antibody</a> production.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> They also appear to play a role in protecting some active <a href="/facts/Promoter_(genetics)/YDYBzLfg">promoters</a> from <a href="/facts/Methylation/EvDMWVW5">methylation</a>.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> The presence of R-loops can also inhibit transcription.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> Additionally, R-loop formation appears to be associated with “open” <a href="/facts/Chromatin/ha0TJheJ">chromatin</a>, characteristic of actively transcribed regions.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h3>R-loops as genetic damage</h3> <p>When unscheduled R-loops form, they can cause damage by a number of different mechanisms.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> Exposed single-stranded <a href="/facts/DNA/nB89Iauz">DNA</a> can come under attack by endogenous mutagens, including DNA-modifying enzymes such as <a href="/facts/Activation-induced_cytidine_deaminase/JKBrRjhl">activation-induced cytidine deaminase</a>, and can block replication forks to induce fork collapse and subsequent double-strand breaks.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> As well, R-loops may induce unscheduled replication by acting as a <a href="/facts/Primer_(molecular_biology)/I3fBfwte">primer</a>.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p><p>R-loop accumulation has been associated with a number of diseases, including <a href="/facts/Amyotrophic_lateral_sclerosis/9fIXnNL4">amyotrophic lateral sclerosis type 4 (ALS4)</a>, <a href="/facts/Oculomotor_apraxia/IRFStbSX">ataxia oculomotor apraxia type 2 (AOA2)</a>, <a href="/facts/Aicardi%25E2%2580%2593Gouti%25C3%25A8res_syndrome/HVwSu5ly">Aicardi–Goutières syndrome</a>, <a href="/facts/Angelman_syndrome/cYSFtQc0">Angelman syndrome</a>, <a href="/facts/Prader%25E2%2580%2593Willi_syndrome/KnyvDSeH">Prader–Willi syndrome</a>, and cancer.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> Genes associated with <a href="/facts/Fanconi_anemia/4p1QUprP">Fanconi anemia</a> also seem to be important for the maintenance of genome stability under conditions where R-loops accumulate.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p> <h2 id="r-loops-introns-and-dna-damage">R-loops, Introns and DNA damage</h2> <p><a href="/facts/Intron/LS6YdBEK">Introns</a> are non-coding regions within <a href="/facts/Gene/e1swwPY6">genes</a> that are transcribed along with the coding regions of genes, but are subsequently removed from the <a href="/facts/Primary_transcript/4UXtKPHw">primary RNA transcript</a> by <a href="/facts/RNA_splicing/a2QEvCRI">splicing</a>. Actively transcribed regions of <a href="/facts/DNA/nB89Iauz">DNA</a> often form R-loops that are vulnerable to <a href="/facts/DNA_damage_(naturally_occurring)/CjGTLKGl">DNA damage</a>. Introns reduce R-loop formation and DNA damage in highly expressed yeast genes.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> Genome-wide analysis showed that intron-containing genes display decreased R-loop levels and decreased DNA damage compared to intron-less genes of similar expression in both yeast and humans.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> Inserting an intron within an R-loop prone gene can also suppress R-loop formation and <a href="/facts/Genetic_recombination/uocNH0m7">recombination</a>. Bonnet et al. (2017)<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> speculated that the function of introns in maintaining genetic stability may explain their evolutionary maintenance at certain locations, particularly in highly expressed genes. </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/DRIP-seq/mtPr1SFt">DRIP-seq</a></li> <li><a href="/facts/Ribonuclease_H/UKaLv8fh">Ribonuclease H</a></li> <li><a href="/facts/Immunoglobulin_class_switching/q8w8PWoY">Immunoglobulin class switching</a></li> <li><a href="/facts/DNA_replication/wrU6RuR3">DNA replication</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Hodson, Charlotte; van Twest, Sylvie; Dylewska, Malgorzata; O’Rourke, Julienne J.; Tan, Winnie; Murphy, Vincent J.; Walia, Mannu; Abbouche, Lara; Nieminuszczy, Jadwiga; Dunn, Elyse; Bythell-Douglas, Rohan; Heierhorst, Jörg; Niedzwiedz, Wojciech; Deans, Andrew J. (2022). 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