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Tepper, S.* ; Mortusewicz, O.* ; Członka, E.* ; Bello, A.* ; Schmidt, A.* ; Jeschke, J.* ; Fischbach, A.* ; Pfeil, I. ; Petersen-Mahrt, S.K.* ; Mangerich, A.* ; Helleday, T.* ; Leonhardt, H.* ; Jungnickel, B.*

Restriction of AID activity and somatic hypermutation by PARP-1.

Nucleic Acids Res. 47, 7418-7429 (2019)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Affinity maturation of the humoral immune response depends on somatic hypermutation (SHM) of immunoglobulin (Ig) genes, which is initiated by targeted lesion introduction by activation-induced deaminase (AID), followed by error-prone DNA repair. Stringent regulation of this process is essential to prevent genetic instability, but no negative feedback control has been identified to date. Here we show that poly(ADP-ribose) polymerase-1 (PARP-1) is a key factor restricting AID activity during somatic hypermutation. Poly(ADP-ribose) (PAR) chains formed at DNA breaks trigger AID-PAR association, thus preventing excessive DNA damage induction at sites of AID action. Accordingly, AID activity and somatic hypermutation at the Ig variable region is decreased by PARP-1 activity. In addition, PARP-1 regulates DNA lesion processing by affecting strand biased A:T mutagenesis. Our study establishes a novel function of the ancestral genome maintenance factor PARP-1 as a critical local feedback regulator of both AID activity and DNA repair during Ig gene diversification.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dna-repair; B-cells; Homologous Recombination; Genomic Instability; Gene Conversion; Deaminase Aid; Strand Bias; Poly(adp-ribose); Mechanisms; Transcription
Sprache englisch
Veröffentlichungsjahr 2019
HGF-Berichtsjahr 2019
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Zeitschrift Nucleic Acids Research
Quellenangaben Band: 47, Heft: 14, Seiten: 7418-7429 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501490-001
DOI 10.1093/nar/gkz466
WOS ID WOS:000483815100026
Scopus ID 85071703542
PubMed ID 31127309
Erfassungsdatum 2019-05-29
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