N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells
R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells 1 – 4 . Here we show that N 6 -methyladenosine (m 6 A) modification, contributing to different aspects of messenger RNA metabolism 5 , 6...
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| Veröffentlicht in: | Nature genetics 2020, Vol.52 (1), p.48-55 |
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| creator | Abakir, Abdulkadir Giles, Tom C. Cristini, Agnese Foster, Jeremy M. Dai, Nan Starczak, Marta Rubio-Roldan, Alejandro Li, Miaomiao Eleftheriou, Maria Crutchley, James Flatt, Luke Young, Lorraine Gaffney, Daniel J. Denning, Chris Dalhus, Bjørn Emes, Richard D. Gackowski, Daniel Corrêa, Ivan R. Garcia-Perez, Jose L. Klungland, Arne Gromak, Natalia Ruzov, Alexey |
| description | R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells
1
–
4
. Here we show that
N
6
-methyladenosine (m
6
A) modification, contributing to different aspects of messenger RNA metabolism
5
,
6
, is detectable on the majority of RNA:DNA hybrids in human pluripotent stem cells. We demonstrate that m
6
A-containing R-loops accumulate during G
2
/M and are depleted at G
0
/G
1
phases of the cell cycle, and that the m
6
A reader promoting mRNA degradation, YTHDF2 (ref.
7
), interacts with R-loop-enriched loci in dividing cells. Consequently,
YTHDF2
knockout leads to increased R-loop levels, cell growth retardation and accumulation of γH2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m
6
A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability.
N
6
-methyladenosine (m
6
A) is prevalent at RNA:DNA hybrids in human pluripotent stem cells. The m
6
A reader YTHDF2 interacts with R-loop-enriched loci in dividing cells, and YTHDF2 loss leads to increased R-loop levels and accumulation of γH2AX. |
| doi_str_mv | 10.1038/s41588-019-0549-x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6974403</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2348899803</sourcerecordid><originalsourceid>FETCH-LOGICAL-p126x-41b8f93eeca1e3ffff196fe2c3ad6ffc136023859f9a6e3c182065c5c798232d3</originalsourceid><addsrcrecordid>eNpVkd9LwzAQx4Mobk7_AN8CPkdzSZolPghj_oQxQfQ5pO117eja2bSy_vd2ThDv5Q7uy4fjPoRcAr8GLs1NUBAZwzhYxiNl2e6IjCFSmsEUzPEwcw1McalH5CyENeegFDenZCTBKCWFHJPFUrMNtnlf-hSrOhQV0gZXXelbDLTNkYbWx0VZtD2tM_q2nN3eL2c07-OmSAMtKpp3G1_RBMsynJOTzJcBL377hHw8PrzPn9ni9ellPluwLQi9Ywpik1mJmHhAmQ0FVmcoEulTnWUJSM2FNJHNrNcoEzCC6yiJkqk1QopUTsjdgbvt4g2mCVZt40u3bYqNb3pX-8L931RF7lb1l9N2OnxADoCrX0BTf3YYWreuu6YabnZCKmOsNT8pcUiFgVytsPlLAXd7A-5gwA0G3N6A28lvMyF48w</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2348899803</pqid></control><display><type>article</type><title>N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells</title><source>Nature</source><source>SpringerLink Journals - AutoHoldings</source><creator>Abakir, Abdulkadir ; Giles, Tom C. ; Cristini, Agnese ; Foster, Jeremy M. ; Dai, Nan ; Starczak, Marta ; Rubio-Roldan, Alejandro ; Li, Miaomiao ; Eleftheriou, Maria ; Crutchley, James ; Flatt, Luke ; Young, Lorraine ; Gaffney, Daniel J. ; Denning, Chris ; Dalhus, Bjørn ; Emes, Richard D. ; Gackowski, Daniel ; Corrêa, Ivan R. ; Garcia-Perez, Jose L. ; Klungland, Arne ; Gromak, Natalia ; Ruzov, Alexey</creator><creatorcontrib>Abakir, Abdulkadir ; Giles, Tom C. ; Cristini, Agnese ; Foster, Jeremy M. ; Dai, Nan ; Starczak, Marta ; Rubio-Roldan, Alejandro ; Li, Miaomiao ; Eleftheriou, Maria ; Crutchley, James ; Flatt, Luke ; Young, Lorraine ; Gaffney, Daniel J. ; Denning, Chris ; Dalhus, Bjørn ; Emes, Richard D. ; Gackowski, Daniel ; Corrêa, Ivan R. ; Garcia-Perez, Jose L. ; Klungland, Arne ; Gromak, Natalia ; Ruzov, Alexey</creatorcontrib><description>R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells
1
–
4
. Here we show that
N
6
-methyladenosine (m
6
A) modification, contributing to different aspects of messenger RNA metabolism
5
,
6
, is detectable on the majority of RNA:DNA hybrids in human pluripotent stem cells. We demonstrate that m
6
A-containing R-loops accumulate during G
2
/M and are depleted at G
0
/G
1
phases of the cell cycle, and that the m
6
A reader promoting mRNA degradation, YTHDF2 (ref.
7
), interacts with R-loop-enriched loci in dividing cells. Consequently,
YTHDF2
knockout leads to increased R-loop levels, cell growth retardation and accumulation of γH2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m
6
A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability.
N
6
-methyladenosine (m
6
A) is prevalent at RNA:DNA hybrids in human pluripotent stem cells. The m
6
A reader YTHDF2 interacts with R-loop-enriched loci in dividing cells, and YTHDF2 loss leads to increased R-loop levels and accumulation of γH2AX.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/s41588-019-0549-x</identifier><identifier>PMID: 31844323</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/208/176 ; 631/208/191 ; 631/208/200 ; 631/337/176 ; 631/337/2019 ; Accumulation ; Adenosine ; Agriculture ; Animal Genetics and Genomics ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell cycle ; Chromatography ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA methylation ; Experiments ; Gene Function ; Genomes ; Genomic instability ; Growth rate ; Human Genetics ; Hybrids ; Letter ; Mammalian cells ; Mammals ; Mass spectrometry ; mRNA ; N6-methyladenosine ; Nucleic acids ; Pluripotency ; Proteins ; R-loops ; Ribonucleic acid ; RNA ; Scientific imaging ; Single-stranded DNA ; Stability ; Stem cells</subject><ispartof>Nature genetics, 2020, Vol.52 (1), p.48-55</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2019</rights><rights>Copyright Nature Publishing Group Jan 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-7259-1511 ; 0000-0002-3169-6878 ; 0000-0002-1529-1862 ; 0000-0002-8132-9849 ; 0000-0001-7274-3661 ; 0000-0001-5043-5529 ; 0000-0002-1247-6634 ; 0000-0001-5107-6513 ; 0000-0002-1842-5838 ; 0000-0001-6855-5481</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41588-019-0549-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41588-019-0549-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27923,27924,41487,42556,51318</link.rule.ids></links><search><creatorcontrib>Abakir, Abdulkadir</creatorcontrib><creatorcontrib>Giles, Tom C.</creatorcontrib><creatorcontrib>Cristini, Agnese</creatorcontrib><creatorcontrib>Foster, Jeremy M.</creatorcontrib><creatorcontrib>Dai, Nan</creatorcontrib><creatorcontrib>Starczak, Marta</creatorcontrib><creatorcontrib>Rubio-Roldan, Alejandro</creatorcontrib><creatorcontrib>Li, Miaomiao</creatorcontrib><creatorcontrib>Eleftheriou, Maria</creatorcontrib><creatorcontrib>Crutchley, James</creatorcontrib><creatorcontrib>Flatt, Luke</creatorcontrib><creatorcontrib>Young, Lorraine</creatorcontrib><creatorcontrib>Gaffney, Daniel J.</creatorcontrib><creatorcontrib>Denning, Chris</creatorcontrib><creatorcontrib>Dalhus, Bjørn</creatorcontrib><creatorcontrib>Emes, Richard D.</creatorcontrib><creatorcontrib>Gackowski, Daniel</creatorcontrib><creatorcontrib>Corrêa, Ivan R.</creatorcontrib><creatorcontrib>Garcia-Perez, Jose L.</creatorcontrib><creatorcontrib>Klungland, Arne</creatorcontrib><creatorcontrib>Gromak, Natalia</creatorcontrib><creatorcontrib>Ruzov, Alexey</creatorcontrib><title>N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><description>R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells
1
–
4
. Here we show that
N
6
-methyladenosine (m
6
A) modification, contributing to different aspects of messenger RNA metabolism
5
,
6
, is detectable on the majority of RNA:DNA hybrids in human pluripotent stem cells. We demonstrate that m
6
A-containing R-loops accumulate during G
2
/M and are depleted at G
0
/G
1
phases of the cell cycle, and that the m
6
A reader promoting mRNA degradation, YTHDF2 (ref.
7
), interacts with R-loop-enriched loci in dividing cells. Consequently,
YTHDF2
knockout leads to increased R-loop levels, cell growth retardation and accumulation of γH2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m
6
A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability.
N
6
-methyladenosine (m
6
A) is prevalent at RNA:DNA hybrids in human pluripotent stem cells. The m
6
A reader YTHDF2 interacts with R-loop-enriched loci in dividing cells, and YTHDF2 loss leads to increased R-loop levels and accumulation of γH2AX.</description><subject>631/208/176</subject><subject>631/208/191</subject><subject>631/208/200</subject><subject>631/337/176</subject><subject>631/337/2019</subject><subject>Accumulation</subject><subject>Adenosine</subject><subject>Agriculture</subject><subject>Animal Genetics and Genomics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell cycle</subject><subject>Chromatography</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA methylation</subject><subject>Experiments</subject><subject>Gene Function</subject><subject>Genomes</subject><subject>Genomic instability</subject><subject>Growth rate</subject><subject>Human Genetics</subject><subject>Hybrids</subject><subject>Letter</subject><subject>Mammalian cells</subject><subject>Mammals</subject><subject>Mass spectrometry</subject><subject>mRNA</subject><subject>N6-methyladenosine</subject><subject>Nucleic acids</subject><subject>Pluripotency</subject><subject>Proteins</subject><subject>R-loops</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Scientific imaging</subject><subject>Single-stranded DNA</subject><subject>Stability</subject><subject>Stem cells</subject><issn>1061-4036</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpVkd9LwzAQx4Mobk7_AN8CPkdzSZolPghj_oQxQfQ5pO117eja2bSy_vd2ThDv5Q7uy4fjPoRcAr8GLs1NUBAZwzhYxiNl2e6IjCFSmsEUzPEwcw1McalH5CyENeegFDenZCTBKCWFHJPFUrMNtnlf-hSrOhQV0gZXXelbDLTNkYbWx0VZtD2tM_q2nN3eL2c07-OmSAMtKpp3G1_RBMsynJOTzJcBL377hHw8PrzPn9ni9ellPluwLQi9Ywpik1mJmHhAmQ0FVmcoEulTnWUJSM2FNJHNrNcoEzCC6yiJkqk1QopUTsjdgbvt4g2mCVZt40u3bYqNb3pX-8L931RF7lb1l9N2OnxADoCrX0BTf3YYWreuu6YabnZCKmOsNT8pcUiFgVytsPlLAXd7A-5gwA0G3N6A28lvMyF48w</recordid><startdate>2020</startdate><enddate>2020</enddate><creator>Abakir, Abdulkadir</creator><creator>Giles, Tom 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regulates the stability of RNA:DNA hybrids in human cells</title><author>Abakir, Abdulkadir ; Giles, Tom C. ; Cristini, Agnese ; Foster, Jeremy M. ; Dai, Nan ; Starczak, Marta ; Rubio-Roldan, Alejandro ; Li, Miaomiao ; Eleftheriou, Maria ; Crutchley, James ; Flatt, Luke ; Young, Lorraine ; Gaffney, Daniel J. ; Denning, Chris ; Dalhus, Bjørn ; Emes, Richard D. ; Gackowski, Daniel ; Corrêa, Ivan R. ; Garcia-Perez, Jose L. ; Klungland, Arne ; Gromak, Natalia ; Ruzov, Alexey</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p126x-41b8f93eeca1e3ffff196fe2c3ad6ffc136023859f9a6e3c182065c5c798232d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>631/208/176</topic><topic>631/208/191</topic><topic>631/208/200</topic><topic>631/337/176</topic><topic>631/337/2019</topic><topic>Accumulation</topic><topic>Adenosine</topic><topic>Agriculture</topic><topic>Animal Genetics and Genomics</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Cell cycle</topic><topic>Chromatography</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA methylation</topic><topic>Experiments</topic><topic>Gene Function</topic><topic>Genomes</topic><topic>Genomic instability</topic><topic>Growth rate</topic><topic>Human Genetics</topic><topic>Hybrids</topic><topic>Letter</topic><topic>Mammalian cells</topic><topic>Mammals</topic><topic>Mass spectrometry</topic><topic>mRNA</topic><topic>N6-methyladenosine</topic><topic>Nucleic acids</topic><topic>Pluripotency</topic><topic>Proteins</topic><topic>R-loops</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Scientific imaging</topic><topic>Single-stranded DNA</topic><topic>Stability</topic><topic>Stem cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Abakir, Abdulkadir</creatorcontrib><creatorcontrib>Giles, Tom C.</creatorcontrib><creatorcontrib>Cristini, Agnese</creatorcontrib><creatorcontrib>Foster, Jeremy M.</creatorcontrib><creatorcontrib>Dai, Nan</creatorcontrib><creatorcontrib>Starczak, Marta</creatorcontrib><creatorcontrib>Rubio-Roldan, Alejandro</creatorcontrib><creatorcontrib>Li, Miaomiao</creatorcontrib><creatorcontrib>Eleftheriou, Maria</creatorcontrib><creatorcontrib>Crutchley, James</creatorcontrib><creatorcontrib>Flatt, Luke</creatorcontrib><creatorcontrib>Young, Lorraine</creatorcontrib><creatorcontrib>Gaffney, Daniel J.</creatorcontrib><creatorcontrib>Denning, Chris</creatorcontrib><creatorcontrib>Dalhus, Bjørn</creatorcontrib><creatorcontrib>Emes, Richard D.</creatorcontrib><creatorcontrib>Gackowski, Daniel</creatorcontrib><creatorcontrib>Corrêa, Ivan R.</creatorcontrib><creatorcontrib>Garcia-Perez, Jose L.</creatorcontrib><creatorcontrib>Klungland, Arne</creatorcontrib><creatorcontrib>Gromak, Natalia</creatorcontrib><creatorcontrib>Ruzov, Alexey</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest 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in human cells</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><date>2020</date><risdate>2020</risdate><volume>52</volume><issue>1</issue><spage>48</spage><epage>55</epage><pages>48-55</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><abstract>R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells
1
–
4
. Here we show that
N
6
-methyladenosine (m
6
A) modification, contributing to different aspects of messenger RNA metabolism
5
,
6
, is detectable on the majority of RNA:DNA hybrids in human pluripotent stem cells. We demonstrate that m
6
A-containing R-loops accumulate during G
2
/M and are depleted at G
0
/G
1
phases of the cell cycle, and that the m
6
A reader promoting mRNA degradation, YTHDF2 (ref.
7
), interacts with R-loop-enriched loci in dividing cells. Consequently,
YTHDF2
knockout leads to increased R-loop levels, cell growth retardation and accumulation of γH2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m
6
A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability.
N
6
-methyladenosine (m
6
A) is prevalent at RNA:DNA hybrids in human pluripotent stem cells. The m
6
A reader YTHDF2 interacts with R-loop-enriched loci in dividing cells, and YTHDF2 loss leads to increased R-loop levels and accumulation of γH2AX.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>31844323</pmid><doi>10.1038/s41588-019-0549-x</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-7259-1511</orcidid><orcidid>https://orcid.org/0000-0002-3169-6878</orcidid><orcidid>https://orcid.org/0000-0002-1529-1862</orcidid><orcidid>https://orcid.org/0000-0002-8132-9849</orcidid><orcidid>https://orcid.org/0000-0001-7274-3661</orcidid><orcidid>https://orcid.org/0000-0001-5043-5529</orcidid><orcidid>https://orcid.org/0000-0002-1247-6634</orcidid><orcidid>https://orcid.org/0000-0001-5107-6513</orcidid><orcidid>https://orcid.org/0000-0002-1842-5838</orcidid><orcidid>https://orcid.org/0000-0001-6855-5481</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1061-4036 |
| ispartof | Nature genetics, 2020, Vol.52 (1), p.48-55 |
| issn | 1061-4036 1546-1718 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6974403 |
| source | Nature; SpringerLink Journals - AutoHoldings |
| subjects | 631/208/176 631/208/191 631/208/200 631/337/176 631/337/2019 Accumulation Adenosine Agriculture Animal Genetics and Genomics Biomedical and Life Sciences Biomedicine Cancer Research Cell cycle Chromatography Deoxyribonucleic acid DNA DNA damage DNA methylation Experiments Gene Function Genomes Genomic instability Growth rate Human Genetics Hybrids Letter Mammalian cells Mammals Mass spectrometry mRNA N6-methyladenosine Nucleic acids Pluripotency Proteins R-loops Ribonucleic acid RNA Scientific imaging Single-stranded DNA Stability Stem cells |
| title | N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T03%3A42%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=N6-methyladenosine%20regulates%20the%20stability%20of%20RNA:DNA%20hybrids%20in%20human%20cells&rft.jtitle=Nature%20genetics&rft.au=Abakir,%20Abdulkadir&rft.date=2020&rft.volume=52&rft.issue=1&rft.spage=48&rft.epage=55&rft.pages=48-55&rft.issn=1061-4036&rft.eissn=1546-1718&rft_id=info:doi/10.1038/s41588-019-0549-x&rft_dat=%3Cproquest_pubme%3E2348899803%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2348899803&rft_id=info:pmid/31844323&rfr_iscdi=true |