Restriction of AID activity and somatic hypermutation by PARP-1 | Zendy

Sandra Tepper | Zendy; Oliver Mortusewicz | Zendy; Ewelina Członka | Zendy; Amanda Bello | Zendy; Angelika Schmidt | Zendy; Julia Jeschke | Zendy; Arthur Fischbach | Zendy; Ines Pfeil | Zendy; Svend K. PetersenMahrt | Zendy; Aswin Mangerich | Zendy; Thomas Helleday | Zendy; Heinrich Leonhardt | Zendy; Berit Jungnickel | Zendy

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Restriction of AID activity and somatic hypermutation by PARP-1

Author(s) -

Sandra Tepper,

Oliver Mortusewicz,

Ewelina Członka,

Amanda Bello,

Angelika Schmidt,

Julia Jeschke,

Arthur Fischbach,

Ines Pfeil,

Svend K. PetersenMahrt,

Aswin Mangerich,

Thomas Helleday,

Heinrich Leonhardt,

Berit Jungnickel

Publication year - 2019

Publication title -

nucleic acids research

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 9.008

H-Index - 537

eISSN - 1362-4954

pISSN - 0305-1048

DOI - 10.1093/nar/gkz466

Subject(s) - somatic hypermutation , biology , mutagenesis , cytidine deaminase , genetics , poly adp ribose polymerase , dna repair , mutation , genome instability , immunoglobulin class switching , gene , dna , somatic cell , dna damage , polymerase , microbiology and biotechnology , antibody , b cell

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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