Restriction of AID activity and somatic hypermutation by PARP-1.
Animals
B-Lymphocytes
/ metabolism
Cell Line, Tumor
Cells, Cultured
Cytidine Deaminase
/ genetics
DNA Damage
DNA Repair
Genes, Immunoglobulin
/ genetics
Humans
Immunoglobulin Variable Region
/ genetics
Mice
Mutation
Poly (ADP-Ribose) Polymerase-1
/ genetics
Somatic Hypermutation, Immunoglobulin
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
22 08 2019
22 08 2019
Historique:
accepted:
16
05
2019
revised:
13
05
2019
received:
19
03
2019
pubmed:
28
5
2019
medline:
18
12
2019
entrez:
26
5
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31127309
pii: 5498626
doi: 10.1093/nar/gkz466
pmc: PMC6698665
doi:
Substances chimiques
Immunoglobulin Variable Region
0
PARP1 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
AICDA (activation-induced cytidine deaminase)
EC 3.5.4.-
Cytidine Deaminase
EC 3.5.4.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7418-7429Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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