PARP activation promotes nuclear AID accumulation in lymphoma cells

Tepper, Sandra; Jeschke, Julia; Böttcher, Katrin; Schmidt, Angelika; Davari, Kathrin; Müller, Peter; Kremmer, Elisabeth; Hemmerich, Peter; Pfeil, Ines; Jungnickel, Berit

doi:10.18632/oncotarget.7603

Cited by 8 publications

(6 citation statements)

References 68 publications

(65 reference statements)

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“…AID localizes to the nucleus in response to DNA damage induced by ionizing radiation and other agents [ 28 , 41 , 42 ]. This raised the possibility that AID nuclear pulses are a response to damage caused by DNA deamination catalyzed by nuclear AID present at levels too low to detect by imaging.…”

Section: Resultsmentioning

confidence: 99%

Activation-induced deaminase (AID) localizes to the nucleus in brief pulses

Maizels

2019

PLoS Genet

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Activation-induced deaminase (AID) converts C to U and 5-methyl-C to T. These mutagenic activities are critical to immunoglobulin (Ig) gene diversification and epigenetic reprogramming, but they must be tightly controlled to prevent compromising cell fitness. AID acts in the nucleus but localizes predominately to the cytoplasm. To address this apparent paradox, we have carried out time-lapse imaging of AID in single living B cells and fibroblasts. We demonstrate that AID enters the nucleus in brief (30 min) pulses, evident in about 10% of cells in the course of a single cell cycle (24 hr imaging). Pulses do not depend on AID catalytic activity, but they are coordinated with nuclear accumulation of P53. Pulsing may protect cells from pathologic consequences of excess exposure to AID, or enable AID to synchronize its activity with transcription of genes that are AID targets or with nuclear entry of factors that act at sites of AID-catalyzed DNA deamination to promote Ig gene diversification or epigenetic reprogramming.

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Section: Resultsmentioning

confidence: 99%

Activation-induced deaminase (AID) localizes to the nucleus in brief pulses

Maizels

2019

PLoS Genet

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“…Recently, it was shown that activation of Parp1 by DNA damage results in reduced proteasomal degradation of AID, and increased nuclear accumulation [42]. YY1 does not regulate expression of Parp1, but our previous RNA transcript data in LPS plus IL4 activated splenic B cells show that YY1 positively regulates Parp2 expression [43].…”

Section: Discussionmentioning

confidence: 77%

Transcription factor YY1 can control AID‐mediated mutagenesis in mice

et al. 2017

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Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1 ) or that express normal AID levels (yy1 ), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sμ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination.

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“…As we previously found that PARP-1 regulates AID localization and stability upon exogenous DNA damage (20), we first asked whether the two enzymes interact in B cells undergoing SHM. Co-immunoprecipitation studies revealed that this is indeed the case: In the hypermutating and AID-expressing cell line Raji (34), immunoprecipitation with an AID antibody co-precipitated PARP-1, while this was not the case in non-mutating and AID low BJAB cells (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Our study was motivated by previous findings in our lab that implicated PARP-1 in the regulation of AID in case of exogenous introduction of DNA damage (20), which led to accumulation and stabilization of AID in the nucleus dependent on PARP-1 activity. Our present results shed more light on the mechanism of these previous findings.…”

Section: Discussionmentioning

confidence: 99%

“…While the molecular mechanisms triggering error-prone instead of error-free repair during SHM are largely elusive to date, mechanisms regulating AID activity are extensively studied and involve expression regulation via various transcription factors and miRNAs, balancing of cellular localization by cytosolic retention and nuclear import factors, as well as regulation of AID’s nuclear stability and its targeting to Ig genes (16–19). We have recently shown that PARP-1 is involved in AID regulation upon exogenous DNA damage, effectively leading to sequestration and stabilization of this mostly cytoplasmic enzyme in the cell nucleus (20). In the present study, we have investigated whether PARP-1 also affects AID regulation in the physiological context of Ig diversification.…”

Section: Introductionmentioning

confidence: 99%

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Restriction of AID activity and somatic hypermutation by PARP-1

Tepper

Mortusewicz

Członka

et al. 2019

Nucleic Acids Research

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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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PARP activation promotes nuclear AID accumulation in lymphoma cells

Cited by 8 publications

References 68 publications

Activation-induced deaminase (AID) localizes to the nucleus in brief pulses

Activation-induced deaminase (AID) localizes to the nucleus in brief pulses

Transcription factor YY1 can control AID‐mediated mutagenesis in mice

Restriction of AID activity and somatic hypermutation by PARP-1

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