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Activation-induced cytidine deaminase (AID) interacts with replication protein A (RPA), the major ssDNA-binding protein, to promote deamination of cytosine to uracil in transcribed immunoglobulin (Ig) genes. Uracil-DNA glycosylase (UNG) acts in concert with AID during Ig diversification. In addition, UNG preserves genome integrity by base-excision repair (BER) in the overall genome. How UNG is regulated to support both mutagenic processing and error-free repair remains unknown. UNG is expressed as two isoforms, UNG1 and UNG2, which both contain an RPA-binding helix that facilitates uracil excision from RPA-coated ssDNA. However, the impact of this interaction in antibody diversification and genome maintenance has not been investigated. Here, we generated B-cell clones with targeted mutations in the UNG RPA-binding motif, and analysed class switch recombination (CSR), mutation frequency (5' Ig Sμ), and genomic uracil in clones representing seven Ung genotypes. We show that the UNG:RPA interaction plays a crucial role in both CSR and repair of AID-induced uracil at the Ig loci. By contrast, the interaction had no significant impact on total genomic uracil levels. Thus, RPA coordinates UNG during CSR and pre-replicative repair of mutagenic uracil in ssDNA but is not essential in post-replicative and canonical BER of uracil in dsDNA.

Titel:	RPA guides UNG to uracil in ssDNA to facilitate antibody class switching and repair of mutagenic uracil at the replication fork.
Autor/in / Beteiligte Person:	Hayran, AB ; Liabakk, NB ; Aas, PA ; Kusnierczyk, A ; Vågbø, CB ; Sarno, A ; Iveland, TS ; Chawla, K ; Zahn, A ; Di Noia, JM ; Slupphaug, G ; Kavli, B
Link:	Zum Volltext
Zeitschrift:	Nucleic acids research, Jg. 52 (2024-01-25), Heft 2, S. 784
Veröffentlichung:	1992- : Oxford : Oxford University Press ; <i>Original Publication</i>: London, Information Retrieval ltd., 2024
Medientyp:	academicJournal
ISSN:	1362-4962 (electronic)
DOI:	10.1093/nar/gkad1115
Schlagwort:	Cytidine Deaminase genetics Cytidine Deaminase metabolism DNA Repair genetics DNA, Single-Stranded genetics Immunoglobulin Class Switching genetics Immunoglobulin Isotypes genetics Immunoglobulins genetics Mutagens Uracil metabolism Humans Animals Mice Replication Protein A genetics Replication Protein A metabolism Uracil-DNA Glycosidase genetics Uracil-DNA Glycosidase metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Nucleic Acids Res] 2024 Jan 25; Vol. 52 (2), pp. 784-800. MeSH Terms: Replication Protein A* / genetics ; Replication Protein A* / metabolism ; Uracil-DNA Glycosidase* / genetics ; Uracil-DNA Glycosidase* / metabolism ; Cytidine Deaminase / genetics ; Cytidine Deaminase / metabolism ; DNA Repair / genetics ; DNA, Single-Stranded / genetics ; Immunoglobulin Class Switching / genetics ; Immunoglobulin Isotypes / genetics ; Immunoglobulins / genetics ; Mutagens ; Uracil / metabolism ; Humans ; Animals ; Mice References: J Biol Chem. 2002 Oct 18;277(42):39926-36. (PMID: 12161446) ; Nat Struct Mol Biol. 2019 Jul;26(7):607-612. (PMID: 31235913) ; Biophys J. 2017 Jul 25;113(2):393-401. (PMID: 28746850) ; Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4102-7. (PMID: 12651944) ; Nature. 2005 Nov 24;438(7067):508-11. (PMID: 16251902) ; Mol Cell Biol. 2014 Nov;34(21):4019-32. (PMID: 25154417) ; J Exp Med. 2005 Jun 20;201(12):2011-21. (PMID: 15967827) ; Nat Biotechnol. 2016 Jul 12;34(7):695-7. (PMID: 27404874) ; DNA Repair (Amst). 2007 Apr 1;6(4):505-16. (PMID: 17116429) ; Nucleic Acids Res. 2019 May 21;47(9):4569-4585. (PMID: 30838409) ; Nucleic Acids Res. 2011 Oct;39(19):8430-44. (PMID: 21745813) ; J Immunol. 2023 May 15;210(10):1508-1518. (PMID: 37000470) ; Carcinogenesis. 2005 Mar;26(3):547-55. (PMID: 15564287) ; Nucleic Acids Res. 2002 Jul 15;30(14):3059-66. (PMID: 12136088) ; Nat Immunol. 2003 Oct;4(10):1023-8. (PMID: 12958596) ; Cell Rep. 2020 Jun 2;31(9):107705. (PMID: 32492421) ; Adv Immunol. 2017;133:37-87. (PMID: 28215280) ; Nat Rev Immunol. 2004 Nov;4(11):868-77. (PMID: 15516966) ; Nucleic Acids Res. 2016 Jul 8;44(12):5758-72. (PMID: 27131385) ; Nat Struct Mol Biol. 2019 Jul;26(7):613-618. (PMID: 31235915) ; J Biol Chem. 2011 May 13;286(19):16669-80. (PMID: 21454529) ; Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2717-22. (PMID: 19196992) ; Cancer Res. 2008 Aug 1;68(15):6118-26. (PMID: 18676834) ; Cell. 2000 Sep 1;102(5):553-63. (PMID: 11007474) ; Nature. 2021 Dec;600(7888):329-333. (PMID: 34819671) ; PLoS Genet. 2015 Sep 10;11(9):e1005411. (PMID: 26355458) ; Nature. 2004 Aug 26;430(7003):992-8. (PMID: 15273694) ; J Exp Med. 2017 Jan;214(1):49-58. (PMID: 27998928) ; Trends Immunol. 2020 Jul;41(7):586-600. (PMID: 32434680) ; Nucleic Acids Res. 2021 Apr 19;49(7):3948-3966. (PMID: 33784377) ; DNA Repair (Amst). 2012 Jun 1;11(6):587-93. (PMID: 22483865) ; Bioessays. 2014 Dec;36(12):1156-61. (PMID: 25171654) ; Genes Dev. 2022 Apr 1;36(7-8):433-450. (PMID: 35450882) ; Curr Biol. 2002 Oct 15;12(20):1748-55. (PMID: 12401169) ; PLoS One. 2016 Oct 5;11(10):e0163962. (PMID: 27706213) ; Cell. 2019 Jan 10;176(1-2):144-153.e13. (PMID: 30554877) ; Mol Cell. 2000 Jun;5(6):1059-65. (PMID: 10912000) ; Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):17242-7. (PMID: 25404348) ; EMBO J. 1999 Jul 1;18(13):3834-44. (PMID: 10393198) ; J Biol Chem. 1997 Mar 7;272(10):6561-6. (PMID: 9045683) ; EMBO J. 2008 Jan 9;27(1):51-61. (PMID: 18079698) ; DNA Repair (Amst). 2020 Oct;94:102905. (PMID: 32818816) ; Biochemistry. 1981 Oct 13;20(21):6092-6. (PMID: 6796110) ; Nature. 2021 Dec;600(7888):324-328. (PMID: 34819670) ; Nat Struct Mol Biol. 2018 Jun;25(6):446-453. (PMID: 29807999) ; Int Immunol. 1996 Feb;8(2):193-201. (PMID: 8671604) ; J Exp Med. 2007 Dec 24;204(13):3209-19. (PMID: 18070939) ; DNA Repair (Amst). 2012 Jun 1;11(6):559-69. (PMID: 22521144) ; DNA Repair (Amst). 2016 Feb;38:110-116. (PMID: 26719140) ; Mol Cell. 2020 Jan 16;77(2):384-394.e4. (PMID: 31806351) Grant Information: PJ-155944 Canada CAPMC CIHR; PJ-155944 Canada CAPMC CIHR Substance Nomenclature: EC 3.5.4.5 (Cytidine Deaminase) ; 0 (DNA, Single-Stranded) ; 0 (Immunoglobulin Isotypes) ; 0 (Immunoglobulins) ; 0 (Mutagens) ; 0 (Replication Protein A) ; 56HH86ZVCT (Uracil) ; EC 3.2.2.- (Uracil-DNA Glycosidase) ; 0 (Rpa1 protein, mouse) Entry Date(s): Date Created: 20231124 Date Completed: 20240201 Latest Revision: 20240201 Update Code: 20240201 PubMed Central ID: PMC10810282

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RPA guides UNG to uracil in ssDNA to facilitate antibody class switching and repair of mutagenic uracil at the replication fork.