Senataxin RNA/DNA helicase promotes replication restart at co-transcriptional R-loops to prevent MUS81-dependent fork degradation.

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.

DNA Helicases*/metabolism ; DNA Helicases*/genetics ; R-Loop Structures* ; DNA Replication* ; RNA Helicases*/metabolism ; RNA Helicases*/genetics ; Multifunctional Enzymes*/metabolism ; Multifunctional Enzymes*/genetics ; DNA-Binding Proteins*/metabolism ; DNA-Binding Proteins*/genetics ; DEAD-box RNA Helicases*/metabolism ; DEAD-box RNA Helicases*/genetics ; Endonucleases*/metabolism ; Endonucleases*/genetics; Humans ; Flap Endonucleases/metabolism ; Flap Endonucleases/genetics ; Transcription, Genetic ; DNA Ligase ATP/metabolism ; DNA Ligase ATP/genetics ; DNA/metabolism ; DNA/genetics

Replication forks stalled at co-transcriptional R-loops can be restarted by a mechanism involving fork cleavage-religation cycles mediated by MUS81 endonuclease and DNA ligase IV (LIG4), which presumably relieve the topological barrier generated by the transcription-replication conflict (TRC) and facilitate ELL-dependent reactivation of transcription. Here, we report that the restart of R-loop-stalled replication forks via the MUS81-LIG4-ELL pathway requires senataxin (SETX), a helicase that can unwind RNA:DNA hybrids. We found that SETX promotes replication fork progression by preventing R-loop accumulation during S-phase. Interestingly, loss of SETX helicase activity leads to nascent DNA degradation upon induction of R-loop-mediated fork stalling by hydroxyurea. This fork degradation phenotype is independent of replication fork reversal and results from DNA2-mediated resection of MUS81-cleaved replication forks that accumulate due to defective replication restart. Finally, we demonstrate that SETX acts in a common pathway with the DEAD-box helicase DDX17 to suppress R-loop-mediated replication stress in human cells. A possible cooperation between these RNA/DNA helicases in R-loop unwinding at TRC sites is discussed.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Nat Commun. 2017 Oct 16;8(1):859. (PMID: 29038466)
Nat Struct Mol Biol. 2013 Mar;20(3):347-54. (PMID: 23396353)
Mol Cell. 2019 Feb 21;73(4):670-683.e12. (PMID: 30639241)
Science. 2007 May 25;316(5828):1160-6. (PMID: 17525332)
Nat Struct Mol Biol. 2012 Mar 04;19(4):417-23. (PMID: 22388737)
Nat Genet. 2004 Mar;36(3):225-7. (PMID: 14770181)
Nat Commun. 2014 Sep 22;5:4990. (PMID: 25241845)
Commun Biol. 2022 Dec 21;5(1):1395. (PMID: 36543851)
Curr Opin Cell Biol. 2021 Jun;70:91-99. (PMID: 33610905)
Cell. 2012 Nov 9;151(4):835-846. (PMID: 23141540)
Nat Rev Mol Cell Biol. 2011 Jul 22;12(8):505-16. (PMID: 21779027)
Genes Dev. 2013 Oct 15;27(20):2227-32. (PMID: 24105744)
Mol Cell. 2011 Jan 7;41(1):21-32. (PMID: 21211720)
Nat Cell Biol. 2011 Mar;13(3):243-53. (PMID: 21317883)
Mol Cell. 2018 Nov 1;72(3):568-582.e6. (PMID: 30344097)
Cell Rep. 2020 Feb 18;30(7):2094-2105.e9. (PMID: 32075754)
DNA Repair (Amst). 2021 Oct;106:103182. (PMID: 34303066)
J Mol Biol. 2017 Oct 27;429(21):3181-3195. (PMID: 27771483)
Proc Natl Acad Sci U S A. 2019 Jan 15;116(3):816-825. (PMID: 30591567)
Mol Cell. 2011 Jun 24;42(6):794-805. (PMID: 21700224)
DNA Repair (Amst). 2014 Jul;19:84-94. (PMID: 24746923)
Cell. 2019 Oct 17;179(3):604-618. (PMID: 31607512)
Nat Struct Mol Biol. 2023 Mar;30(3):348-359. (PMID: 36864174)
Nat Commun. 2021 Jul 22;12(1):4451. (PMID: 34294712)
Am J Hum Genet. 2004 Jun;74(6):1128-35. (PMID: 15106121)
Mol Cell. 2017 Jun 1;66(5):658-671.e8. (PMID: 28575661)
Nat Commun. 2023 Mar 30;14(1):1791. (PMID: 36997515)
Sci Adv. 2024 Feb 9;10(6):eadk2685. (PMID: 38324687)
Nat Rev Mol Cell Biol. 2020 Oct;21(10):633-651. (PMID: 32612242)
Mol Cell. 2015 Feb 19;57(4):636-647. (PMID: 25699710)
Nat Commun. 2017 Oct 16;8(1):860. (PMID: 29038425)
Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):. (PMID: 35042798)
Nucleic Acids Res. 2022 Nov 28;50(21):12274-12290. (PMID: 36453994)
Nat Struct Mol Biol. 2020 May;27(5):424-437. (PMID: 32398827)
Mol Cell. 2020 Feb 6;77(3):528-541.e8. (PMID: 31759821)
Cell. 2011 May 13;145(4):529-42. (PMID: 21565612)
Mol Cell Biol. 2013 Jan;33(2):406-17. (PMID: 23149945)
Mol Cell. 2022 Jun 16;82(12):2267-2297. (PMID: 35508167)
Sci Adv. 2020 Nov 13;6(46):. (PMID: 33188024)
Cell Death Discov. 2023 May 5;9(1):145. (PMID: 37147318)
Nature. 2015 Dec 10;528(7581):286-90. (PMID: 26633632)
J Cell Biol. 1998 Mar 23;140(6):1285-95. (PMID: 9508763)
Nucleic Acids Res. 2023 Apr 11;51(6):2818-2837. (PMID: 36864660)
Cell. 2017 Aug 10;170(4):774-786.e19. (PMID: 28802045)
Nat Immunol. 2015 May;16(5):485-94. (PMID: 25822250)
Nat Cell Biol. 2014 Jan;16(1):2-9. (PMID: 24366029)
PLoS Genet. 2015 Nov 19;11(11):e1005674. (PMID: 26584049)
Nat Struct Mol Biol. 2013 Apr;20(4):412-8. (PMID: 23552296)
J Cell Biol. 2013 Jan 21;200(2):173-86. (PMID: 23337116)

KFS-5484-02-2022 Swiss Cancer League; 22-08294S Czech Science Foundation; Foundation for Research in Science; University of Zurich; 310030_184716 Switzerland SNSF_ Swiss National Science Foundation; 310030_192490 Switzerland SNSF_ Swiss National Science Foundation

EC 3.6.4.- (DNA Helicases)
EC 3.6.4.13 (RNA Helicases)
EC 3.6.1.- (SETX protein, human)
0 (Multifunctional Enzymes)
0 (DNA-Binding Proteins)
EC 3.6.4.13 (DEAD-box RNA Helicases)
EC 3.1.- (Endonucleases)
EC 3.1.- (MUS81 protein, human)
EC 3.1.- (Flap Endonucleases)
EC 6.5.1.1 (DNA Ligase ATP)
9007-49-2 (DNA)

Date Created: 20240809 Date Completed: 20240923 Latest Revision: 20240925

20240925

PMC11417401

10.1093/nar/gkae673

39119900