Poly-(ADP-ribose) serves as a scaffold for the methyltransferase METTL3/14 complex in the DNA damage response.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Methyltransferases*/metabolism ; Methyltransferases*/genetics ; DNA Damage* ; DNA Repair* ; Poly Adenosine Diphosphate Ribose*/metabolism; Humans ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly (ADP-Ribose) Polymerase-1/genetics ; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; RNA/metabolism ; Cell Line, Tumor

PARP1, a crucial DNA break sensor, synthesizes poly-(ADP-ribose) (PAR), a nucleic acid that promotes the recruitment of DNA repair proteins. Emerging evidence highlights a role of RNA and RNA-binding proteins in DNA repair. Notably, the RNA-m6A methyltransferase complex METTL3/14 is implicated in repairing ultraviolet-induced DNA lesions. Here, we dissected the interplay between the two nucleic acids PAR and RNA and how METTL3/14 recruitment and m6A accumulation at laser-induced DNA lesions responds to PAR dynamics. In vitro, METTL3/14 recognized both PAR and RNA, yet PAR presence did not inhibit the methyltransferase complex's catalytic activity. Acute knock-out of METTL3 rendered cells sensitive to transcription-blocking DNA damage and resulted in defects in transcription recovery and transcription-coupled DNA repair. Furthermore, combining METTL3 and PARP inhibitors led to an enhanced antiproliferative effect on cancer cells. Future therapeutic avenues may thus leverage the interplay between the nucleic acids PAR and RNA.
(© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Proteome Sci. 2010 Apr 13;8:22. (PMID: 20388209)
Nat Commun. 2022 Aug 13;13(1):4762. (PMID: 35963869)
Mol Cell. 2016 Jul 21;63(2):306-317. (PMID: 27373337)
FEBS Lett. 1987 Mar 23;213(2):309-15. (PMID: 2951275)
BMC Mol Biol. 2007 Oct 25;8:96. (PMID: 17961220)
Bio Protoc. 2023 Feb 05;13(3):. (PMID: 36816995)
Nat Chem Biol. 2014 Feb;10(2):93-5. (PMID: 24316715)
Nature. 2016 May 25;534(7608):575-8. (PMID: 27281194)
Nature. 2014 Jan 2;505(7481):117-20. (PMID: 24284625)
Cell Res. 2017 Oct;27(10):1216-1230. (PMID: 28914256)
Biochem Biophys Res Commun. 2001 Jul 6;285(1):27-31. (PMID: 11437367)
Science. 2017 Mar 17;355(6330):1152-1158. (PMID: 28302823)
Cell Rep. 2018 May 8;23(6):1891-1905. (PMID: 29742442)
Br J Cancer. 2020 Mar;122(5):613-623. (PMID: 31894141)
Nat Commun. 2015 Aug 19;6:8088. (PMID: 26286827)
Trends Cell Biol. 2021 May;31(5):359-371. (PMID: 33685798)
Mol Cell. 2012 Apr 27;46(2):212-25. (PMID: 22424773)
Nature. 2017 Dec 7;552(7683):126-131. (PMID: 29186125)
Mol Cell. 2020 Dec 3;80(5):862-875.e6. (PMID: 33275888)
Nature. 2021 May;593(7860):597-601. (PMID: 33902106)
Cell. 2013 Dec 19;155(7):1479-91. (PMID: 24360272)
Nucleic Acids Res. 2019 Jun 20;47(11):5658-5669. (PMID: 31216043)
Nucleic Acids Res. 2018 Jul 6;46(12):6087-6098. (PMID: 29733391)
Mol Biol Cell. 2016 Dec 1;27(24):3791-3799. (PMID: 27733626)
Nat Chem Biol. 2014 Nov;10(11):927-9. (PMID: 25242552)
Nucleic Acids Res. 2004 Sep 08;32(16):4786-803. (PMID: 15356296)
Mol Cell. 2020 Aug 6;79(3):425-442.e7. (PMID: 32615088)
Nucleic Acids Res. 2022 Jan 11;50(1):449-457. (PMID: 34908152)
Mol Cell Proteomics. 2008 Nov;7(11):2279-87. (PMID: 18622019)
Cancer Commun (Lond). 2024 Feb;44(2):282-286. (PMID: 38102821)
Nat Cell Biol. 2021 Jun;23(6):595-607. (PMID: 34108663)
Oncogene. 1996 Aug 15;13(4):823-31. (PMID: 8761304)
J Am Chem Soc. 2021 Mar 3;143(8):3037-3042. (PMID: 33596067)
Mol Cell. 2013 Oct 24;52(2):272-85. (PMID: 24055347)
Genes Dev. 2017 May 15;31(10):990-1006. (PMID: 28637692)
Nat Cell Biol. 2017 Dec;19(12):1400-1411. (PMID: 29180822)
Cell. 2004 Mar 5;116(5):683-98. (PMID: 15006351)
Nucleic Acids Res. 2017 Jul 27;45(13):7984-7996. (PMID: 28575444)
Proc Natl Acad Sci U S A. 2023 Oct 10;120(41):e2304534120. (PMID: 37782793)
Comput Struct Biotechnol J. 2015 Sep 25;13:504-13. (PMID: 26949479)
Nucleic Acids Res. 2007;35(21):e143. (PMID: 17991682)
Nucleic Acids Res. 2021 Jan 11;49(1):269-284. (PMID: 33313823)
Nat Cell Biol. 2019 Oct;21(10):1286-1299. (PMID: 31570834)
Nat Rev Mol Cell Biol. 2017 Oct;18(10):610-621. (PMID: 28676700)
Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2208860120. (PMID: 36893274)
Nat Struct Mol Biol. 2009 Sep;16(9):923-9. (PMID: 19680243)
Nat Struct Mol Biol. 2017 Jul;24(7):561-569. (PMID: 28581511)
Nat Chem Biol. 2011 Oct 16;7(12):885-7. (PMID: 22002720)
Elife. 2022 May 03;11:. (PMID: 35502895)
J Biol Chem. 2013 Apr 19;288(16):11348-57. (PMID: 23493398)
Nucleic Acids Res. 2021 Nov 18;49(20):11629-11642. (PMID: 34086966)
Biochemistry. 2018 Jan 30;57(4):429-440. (PMID: 29327913)
IEEE Trans Image Process. 1998;7(1):27-41. (PMID: 18267377)
Cell Res. 2019 Mar;29(3):233-247. (PMID: 30728452)
Nature. 2012 Apr 29;485(7397):201-6. (PMID: 22575960)
Mol Cell. 2013 Jan 10;49(1):18-29. (PMID: 23177736)
Nature. 2017 Mar 23;543(7646):573-576. (PMID: 28297716)
Nucleic Acids Res. 2022 Sep 9;50(16):9426-9441. (PMID: 36018800)
DNA Repair (Amst). 2021 Oct;106:103172. (PMID: 34298489)
Cell. 2004 Dec 17;119(6):803-14. (PMID: 15607977)
Cell. 2012 Jun 22;149(7):1635-46. (PMID: 22608085)
Genes Dev. 2024 Oct 16;38(17-20):915-930. (PMID: 39362776)
Science. 2016 Jul 1;353(6294):45-50. (PMID: 27256882)
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1759-E1768. (PMID: 29432179)
Nat Commun. 2023 Sep 30;14(1):6114. (PMID: 37777505)
Nucleic Acids Res. 2020 Jul 2;48(W1):W488-W493. (PMID: 32246720)
Epigenetics Chromatin. 2019 Feb 18;12(1):15. (PMID: 30777121)
Nature. 2018 Aug;560(7716):117-121. (PMID: 30022168)
J Hematol Oncol. 2022 Jan 22;15(1):10. (PMID: 35065680)
Elife. 2016 Sep 14;5:. (PMID: 27627798)
Nature. 2012 Aug 9;488(7410):231-5. (PMID: 22722852)
Genomics Proteomics Bioinformatics. 2016 Jun;14(3):131-139. (PMID: 27240471)
Cell. 2020 Jul 23;182(2):481-496.e21. (PMID: 32649862)
Mol Cell. 2010 Jul 9;39(1):8-24. (PMID: 20603072)
DNA Repair (Amst). 2002 Dec 5;1(12):1027-38. (PMID: 12531012)
Biochem Biophys Res Commun. 2009 May 8;382(3):497-502. (PMID: 19281796)
Nat Rev Genet. 2023 Mar;24(3):143-160. (PMID: 36261710)
J Cell Sci. 2020 May 11;133(9):. (PMID: 32184266)
Cell Rep. 2019 May 7;27(6):1809-1821.e5. (PMID: 31067465)
Nucleic Acids Res. 2023 Mar 21;51(5):2215-2237. (PMID: 36794853)
Elife. 2022 Jan 21;11:. (PMID: 35060905)
Nat Med. 2001 Aug;7(8):961-6. (PMID: 11479630)

213249687 - SFB 1064 Deutsche Forschungsgemeinschaft; 812829 European Union's Horizon 2020; VI.C.212.005 Vici; Netherlands Organization for Scientific Research

EC 2.1.1.- (Methyltransferases)
EC 2.1.1.62 (METTL3 protein, human)
26656-46-2 (Poly Adenosine Diphosphate Ribose)
EC 2.1.1.- (METTL14 protein, human)
EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
0 (Poly(ADP-ribose) Polymerase Inhibitors)
EC 2.4.2.30 (PARP1 protein, human)
63231-63-0 (RNA)

Date Created: 20250412 Date Completed: 20250412 Latest Revision: 20250415

20250415

PMC11992677

10.1093/nar/gkaf244

40219966