دورية أكاديمية
أعرض في EDS

ATR phosphorylates DHX9 at serine 321 to suppress R-loop accumulation upon genotoxic stress.

التفاصيل البيبلوغرافية
العنوان: ATR phosphorylates DHX9 at serine 321 to suppress R-loop accumulation upon genotoxic stress.
المؤلفون: Liu MY; Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan., Lin KR; Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan., Chien YL; Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan., Yang BZ; Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan., Tsui LY; Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan., Chu HC; Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106319, Taiwan., Wu CP; Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan.
المصدر: Nucleic acids research [Nucleic Acids Res] 2024 Jan 11; Vol. 52 (1), pp. 204-222.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: 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
أسماء مطبوعة: Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
مواضيع طبية MeSH: R-Loop Structures* , Serine*/metabolism, Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; DNA Damage ; DNA Replication ; Phosphorylation ; RNA/metabolism ; Humans
مستخلص: Aberrant DNA/RNA hybrids (R-loops) formed during transcription and replication disturbances pose threats to genome stability. DHX9 is an RNA helicase involved in R-loop resolution, but how DHX9 is regulated in response to genotoxic stress remains unclear. Here we report that DHX9 is phosphorylated at S321 and S688, with S321 phosphorylation primarily induced by ATR after DNA damage. Phosphorylation of DHX9 at S321 promotes its interaction with γH2AX, BRCA1 and RPA, and is required for its association with R-loops under genotoxic stress. Inhibition of ATR or expression of the non-phosphorylatable DHX9S321A prevents DHX9 from interacting with RPA and R-loops, leading to the accumulation of stress-induced R-loops. Furthermore, depletion of RPA reduces the association between DHX9 and γH2AX, and in vitro binding analysis confirms a direct interaction between DHX9 and RPA. Notably, cells with the non-phosphorylatable DHX9S321A variant exhibit hypersensitivity to genotoxic stress, while those expressing the phosphomimetic DHX9S321D variant prevent R-loop accumulation and display resistance to DNA damage agents. In summary, we uncover a new mechanism by which ATR directly regulates DHX9 through phosphorylation to eliminate stress-induced R-loops.
(© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
References: Cell Rep. 2018 Jan 23;22(4):1031-1039. (PMID: 29386125)
Nucleic Acids Res. 2021 Sep 7;49(15):8573-8591. (PMID: 34329467)
Cell. 2012 Nov 9;151(4):835-846. (PMID: 23141540)
Genes Dev. 2021 Dec 1;35(23-24):1579-1594. (PMID: 34819354)
EMBO J. 2017 May 2;36(9):1182-1198. (PMID: 28314779)
DNA Repair (Amst). 2011 Jun 10;10(6):654-65. (PMID: 21561811)
Nucleic Acids Res. 2017 Sep 6;45(15):8859-8872. (PMID: 28666352)
Genes Dev. 2017 Jul 1;31(13):1370-1381. (PMID: 28790157)
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19855-60. (PMID: 18077418)
Trends Cell Biol. 2015 Sep;25(9):514-22. (PMID: 26045257)
Cell Rep. 2018 May 8;23(6):1891-1905. (PMID: 29742442)
Science. 2007 May 25;316(5828):1160-6. (PMID: 17525332)
Mol Cell Proteomics. 2010 Jun;9(6):1314-23. (PMID: 20164059)
Nature. 2014 Jul 17;511(7509):362-5. (PMID: 24896180)
Genes Dev. 2012 Jan 15;26(2):163-75. (PMID: 22279048)
Mol Cell. 2017 Jun 15;66(6):801-817. (PMID: 28622525)
Cancers (Basel). 2020 Mar 16;12(3):. (PMID: 32187976)
Cell. 1997 Sep 19;90(6):1107-12. (PMID: 9323138)
J Biol Chem. 1999 Dec 31;274(53):37538-43. (PMID: 10608806)
Nucleic Acids Res. 2013 Dec;41(22):10345-57. (PMID: 24049074)
Oncotarget. 2016 Jul 5;7(27):42716-42739. (PMID: 27034008)
Mol Cell. 2017 Mar 2;65(5):832-847.e4. (PMID: 28257700)
Genes Dev. 2014 Jul 1;28(13):1384-96. (PMID: 24990962)
Mol Cell. 2011 Jun 24;42(6):794-805. (PMID: 21700224)
Cell. 2019 Oct 17;179(3):604-618. (PMID: 31607512)
PLoS Genet. 2014 Sep 18;10(9):e1004630. (PMID: 25233079)
Proc Natl Acad Sci U S A. 2023 Apr 4;120(14):e2300150120. (PMID: 36996117)
Bioessays. 2005 Apr;27(4):397-407. (PMID: 15770685)
Mol Cell. 2009 Jul 31;35(2):228-39. (PMID: 19647519)
Nat Rev Genet. 2015 Oct;16(10):583-97. (PMID: 26370899)
Mol Cell. 2014 Dec 18;56(6):777-85. (PMID: 25435140)
Nat Protoc. 2019 Jun;14(6):1734-1755. (PMID: 31053798)
PLoS Genet. 2014 Apr 17;10(4):e1004288. (PMID: 24743342)
Nucleic Acids Res. 2021 Sep 20;49(16):9424-9443. (PMID: 34365507)
Nat Genet. 1998 Jul;19(3):254-6. (PMID: 9662397)
J Biol Chem. 2021 Jan-Jun;296:100633. (PMID: 33819479)
Science. 2005 Apr 22;308(5721):551-4. (PMID: 15790808)
Mol Cell. 2012 Apr 27;46(2):115-24. (PMID: 22541554)
Mol Cell. 2015 Feb 19;57(4):636-647. (PMID: 25699710)
Nucleic Acids Res. 2022 Nov 28;50(21):12274-12290. (PMID: 36453994)
Nat Commun. 2021 Jul 5;12(1):4126. (PMID: 34226554)
Nature. 2017 Apr 6;544(7648):115-119. (PMID: 28355180)
Mol Cell. 2015 Nov 5;60(3):351-61. (PMID: 26593718)
Nucleic Acids Res. 2019 Jun 4;47(10):5086-5099. (PMID: 30982901)
Proc Natl Acad Sci U S A. 1985 May;82(10):3262-6. (PMID: 2860667)
Nat Immunol. 2003 May;4(5):442-51. (PMID: 12679812)
Nat Commun. 2014 Oct 21;5:5220. (PMID: 25330849)
Cell Rep. 2017 Oct 10;21(2):546-558. (PMID: 29020638)
J Clin Invest. 2021 Feb 1;131(3):. (PMID: 33529165)
DNA Repair (Amst). 2014 May;17:21-9. (PMID: 24680878)
Mol Cell. 2010 Oct 22;40(2):179-204. (PMID: 20965415)
Nucleic Acids Res. 2010 Aug;38(14):4722-30. (PMID: 20385589)
Nat Med. 2017 Apr;23(4):461-471. (PMID: 28263311)
Nat Commun. 2021 Nov 5;12(1):6412. (PMID: 34741010)
Mol Cell. 2022 Jun 16;82(12):2267-2297. (PMID: 35508167)
Mol Cell. 2014 Jan 23;53(2):235-246. (PMID: 24332808)
J Immunol Methods. 1986 May 1;89(1):123-30. (PMID: 2422282)
J Biol Chem. 2005 Mar 11;280(10):9586-94. (PMID: 15613478)
Mol Cell. 2011 Jan 7;41(1):21-32. (PMID: 21211720)
Cell Res. 2015 Jan;25(1):9-23. (PMID: 25403473)
PLoS Genet. 2015 Nov 19;11(11):e1005674. (PMID: 26584049)
معلومات مُعتمدة: 110-2628-B-002-037 National Science and Technology Council; 110L7755 National Taiwan University; National Taiwan University College of Medicine
المشرفين على المادة: EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
63231-63-0 (RNA)
452VLY9402 (Serine)
EC 2.7.11.1 (ATR protein, human)
EC 3.6.1.- (DHX9 protein, human)
تواريخ الأحداث: Date Created: 20231106 Date Completed: 20240122 Latest Revision: 20240122
رمز التحديث: 20240122
مُعرف محوري في PubMed: PMC10783509
DOI: 10.1093/nar/gkad973
PMID: 37930853
قاعدة البيانات: MEDLINE
الوصف
تدمد:1362-4962
DOI:10.1093/nar/gkad973