Restriction of AID activity and somatic hypermutation by PARP-1

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

doi:10.1093/nar/gkz466

Cited by 10 publications

(6 citation statements)

References 58 publications

(59 reference statements)

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“…However, germinal center formation upon immunization is normal in mice with single or dual deficiencies of PARP-1 and PARP-2 [36]. Meanwhile, the role of PARP-1 in SHM is controversial, with some data showing a dispensable role [47], while other data indicate a role of PARP-1 in SHM [48]. Meanwhile, the role of PARP-2 in SHM is unknown.…”

Section: Impact Of Parp-1 and Parp-2 On B Cell Development And Functionmentioning

confidence: 99%

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Yélamos

Moreno-Lama

Jimeno

et al. 2020

Cancers

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Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which posttranslationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein function. Many targets of PARP-1/2-dependent PARylation are involved in the DNA damage response and hence, the loss of these proteins disrupts a wide range of biological processes, from DNA repair and epigenetics to telomere and centromere regulation. The central role of these PARPs in DNA metabolism in cancer cells has led to the development of PARP inhibitors as new cancer therapeutics, both as adjuvant treatment potentiating chemo-, radio-, and immuno-therapies and as monotherapy exploiting cancer-specific defects in DNA repair. However, a cancer is not just made up of cancer cells and the tumor microenvironment also includes multiple other cell types, particularly stromal and immune cells. Interactions between these cells-cancerous and non-cancerous-are known to either favor or limit tumorigenesis. In recent years, an important role of PARP-1 and PARP-2 has been demonstrated in different aspects of the immune response, modulating both the innate and adaptive immune system. It is now emerging that PARP-1 and PARP-2 may not only impact cancer cell biology, but also modulate the anti-tumor immune response. Understanding the immunomodulatory roles of PARP-1 and PARP-2 may provide invaluable clues to the rational development of more selective PARP-centered therapies which target both the cancer and its microenvironment.

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Section: Impact Of Parp-1 and Parp-2 On B Cell Development And Functionmentioning

confidence: 99%

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Yélamos

Moreno-Lama

Jimeno

et al. 2020

Cancers

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“…Most significantly, inhibition of PARP1 leads to the induction of DNA damage and cytotoxicity [356,357] and mitochondrial dysfunction [358] through the upregulation of aerobic glycolysis [359][360][361], which are implicated in the etiology of various metabolic disorders and cancer. Moreover, inflammation inhibits PARP1-dependent DNA repair [359,362,363] and depletion of PARP1 not only triggers sustained induction of interferonstimulated genes (ISGs) [364] and senescence [365] but also exacerbates autoimmune diseases [366][367][368] and spontaneous cancer formation through accelerated aging [369]. In this context, it is interesting to note that inflammation also drives the cleavage of TyrRS [297], indicating a potential role of full-length TyrRS in PARP1-mediated DNA repair [359,362,363].…”

Section: Cisand Trans-rsv Have Opposite Effects On Tyrrs-regulated Pamentioning

confidence: 99%

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

2020

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Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADPribose polymerase 1 (PARP1), a major determinant of cellular NAD +-dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the autopoly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention. Keywords Resveratrol (RSV). Aminoacyl-tRNA synthetases (aaRSs). Tyrosyl-tRNA synthetase (YARS. TyrRS). Nicotinamide adenine nucleotide (NAD +). Poly-ADP-ribose polymerase (PARP). Sirtuins (SIRT). AMP-activated protein kinase (AMPK). Nicotinamide (NAM) GeroScience

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“…Affinity maturation of antibodies is characterized as somatic hypermutation and class-switch recombination which require AID. However, AID activity is restricted in the presence of PARP-1 at Ig loci due to its mutagenic repair function, leading to a decrease of the number of somatic hypermutations (Paddock et al, 2010;Tepper et al, 2019) . This can be an explanation for the lower mean number of non-synonymous SHM in the MBM subset compared to that in the MBG subset in our dataset, even though they were both activated memory B cells.…”

Section: Discussionmentioning

confidence: 99%

The humoral response to BK polyomavirus in kidney transplant recipients is dominated by IgM antibodies that use a distinct repertoire compared to IgG against the same antigen

Ngoc-Khanh

Laetitia

Marie-Claire

et al. 2021

Preprint

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The BK polyomavirus (BKPyV) persists asymptomatically in the kidney and active replication is only seen in immunosuppressed individuals, such as kidney transplant (KTx) recipients, in whom BKPyV reactivation can cause significant morbidity. KTx recipients with BKPyV reactivation mount a robust humoral response, but this often fails to clear the virus. In order to characterize the BKPyV-specific B-cell receptor (BCR) repertoire in KTx recipients, we used fluorescence-labeled BKPyV virus-like particles (VLPs) to sort with BKPyV-specific B-cells, then single-cell RNAseq to obtain paired heavy and light chain antibody sequences, and gene transcriptome data. The BCR repertoire was highly diverse in terms of both V-gene usage and clonotype diversity, with approximately 3% repertoire overlap between patients. The BKPyV-specific response was characterized by the presence of both memory IgG and memory IgM B-cells with extensive somatic hypermutation, which expressed distinct BCR repertoires within the same patient. The gene expression profile of IgG and IgM memory B-cells was highly similar, with only 19 genes, including CD83, CD79A and PARP1 showing significant differential expression. These results confirm that the IgM memory B-cells are a significant component of the BKPyV-specific humoral response, and show for the first time that IgG and IgM repertoires directed against the same antigen can have significant differences.

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Restriction of AID activity and somatic hypermutation by PARP-1

Cited by 10 publications

References 58 publications

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

The humoral response to BK polyomavirus in kidney transplant recipients is dominated by IgM antibodies that use a distinct repertoire compared to IgG against the same antigen

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