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Restriction of AID ...
Restriction of AID activity and somatic hypermutation by PARP-1
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Tepper, S (author)
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- Mortusewicz, O (author)
- Karolinska Institutet
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Czlonka, E (author)
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Bello, A (author)
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Schmidt, A (author)
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Jeschke, J (author)
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Fischbach, A (author)
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Pfeil, I (author)
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Petersen-Mahrt, SK (author)
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Mangerich, A (author)
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- Helleday, T (author)
- Karolinska Institutet
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Leonhardt, H (author)
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Jungnickel, B (author)
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(creator_code:org_t)
- 2019-05-25
- 2019
- English.
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In: Nucleic acids research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 47:14, s. 7418-7429
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Abstract
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- 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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- art (subject category)
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- By the author/editor
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Tepper, S
-
Mortusewicz, O
-
Czlonka, E
-
Bello, A
-
Schmidt, A
-
Jeschke, J
-
show more...
-
Fischbach, A
-
Pfeil, I
-
Petersen-Mahrt, ...
-
Mangerich, A
-
Helleday, T
-
Leonhardt, H
-
Jungnickel, B
-
show less...
- Articles in the publication
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Nucleic acids re ...
- By the university
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Karolinska Institutet