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Tepper S, Mortusewicz O, Członka E, Bello A, Schmidt A, Jeschke J, Fischbach A, Pfeil I, Petersen-Mahrt SK, Mangerich A, Helleday T, Leonhardt H, Jungnickel B
Nucleic Acids Res. 47 (14) 7418-7429 [2019-08-22; online 2019-05-28]
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.
PubMed 31127309
DOI 10.1093/nar/gkz466
Crossref 10.1093/nar/gkz466
pmc: PMC6698665
pii: 5498626