The BRCT Domain of PARP-1 Is Required for Immunoglobulin Gene Conversion

Paddock, Marcia N.; Buelow, Ben; Takeda, Shunichi; Scharenberg, Andrew M.

doi:10.1371/journal.pbio.1000428

Cited by 28 publications

(30 citation statements)

References 40 publications

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“…2A), probably by activating the transcription rate through histone acetylation (37). TSA augments GCV significantly in GANP +/+ DT40 cells, serving as a positive control and validating GCV data in our assay system compared with other laboratories (37,(44)(45)(46). The change in the gene dosage for endogenous GANP (GANP +/+ versus GANP +/2 cells) affected IgV L GCV induced by TSA.…”

Section: Ganp Is Required For Igv L Gcv In Dt40 B Cellssupporting

confidence: 75%

GANP Regulates the Choice of DNA Repair Pathway by DNA-PKcs Interaction in AID-Dependent IgV Region Diversification

Eid

Maeda

Almofty

et al. 2014

The Journal of Immunology

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RNA export factor germinal center–associated nuclear protein (GANP) interacts with activation-induced cytidine deaminase (AID) and shepherds it from the cytoplasm to the nucleus and toward the IgV region loci in B cells. In this study, we demonstrate a role for GANP in the repair of AID-initiated DNA damage in chicken DT40 B cells to generate IgV region diversity by gene conversion and somatic hypermutation. GANP plays a positive role in IgV region diversification of DT40 B cells in a nonhomologous end joining–proficient state. DNA-PKcs physically interacts with GANP, and this interaction is dissociated by dsDNA breaks induced by a topoisomerase II inhibitor, etoposide, or AID overexpression. GANP affects the choice of DNA repair mechanism in B cells toward homologous recombination rather than nonhomologous end joining repair. Thus, GANP presumably plays a critical role in protection of the rearranged IgV loci by favoring homologous recombination of the DNA breaks under accelerated AID recruitment.

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Section: Ganp Is Required For Igv L Gcv In Dt40 B Cellssupporting

confidence: 75%

GANP Regulates the Choice of DNA Repair Pathway by DNA-PKcs Interaction in AID-Dependent IgV Region Diversification

Eid

Maeda

Almofty

et al. 2014

The Journal of Immunology

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“…By using the ER␣ deletion mutants, we observed that endogenous PARP1 associated specifically with the DBD of ER␣. It has been reported that the BRCA1 C terminus (BRCT)/AMD of PARP1 is involved in directing proteinprotein interactions (23). Consistent with such a notion, we localized the ER␣-binding site to the central BRCT/AMD of PARP1 by using PARP1 deletion mutants.…”

Section: Discussionsupporting

confidence: 65%

“…Preparation of Whole Extracts and Nuclear Extracts-Methods for preparation of whole cell extracts and nuclear extracts were described previously (22,23). These whole cell and nuclear extracts were stored at Ϫ80°C until use.…”

Section: Methodsmentioning

confidence: 99%

Poly(ADP-ribose) Polymerase 1 Is a Key Regulator of Estrogen Receptor α-dependent Gene Transcription

Zhang

Yan

Wang

et al. 2013

Journal of Biological Chemistry

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Background: Poly(ADP-ribose) polymerase 1 (PARP1) exerts important functions in transcriptional regulation of transcription factors. Results: PAPR1 interacts with estrogen receptor ␣ (ER␣), and poly(ADP-ribosyl)ation promotes ER␣ transactivation. Conclusion: PARP1 is a crucial regulator of ER␣-dependent gene transcription. Significance: This might be the first study examining the interpaly between PARP1 and ER␣, and identifies that PARP1 controls ER␣ transactivation.

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“…Recently, we have shown that PARP-1 has a distinct role in promoting vertebrate somatic IgH and IgL gene diversification through GCV by inhibiting high-fidelity repair of AID-induced lesions thus directing repair through mutagenic pathways [4]. This role was found to be dependent on PARP-1's BRCT domain, which is not required for high-fidelity base excision repair [4].…”

Section: Introductionmentioning

confidence: 99%

Competition between PARP-1 and Ku70 control the decision between high-fidelity and mutagenic DNA repair

et al. 2011

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Affinity maturation of antibodies requires a unique process of targeted mutation that allows changes to accumulate in the antibody genes while the rest of the genome is protected from off-target mutations that can be oncogenic. This targeting requires that the same deamination event be repaired either by a mutagenic or a high-fidelity pathway depending on the genomic location. We have previously shown that the BRCT domain of the DNA-damage sensor PARP-1 is required for mutagenic repair occurring in the context of IgH and IgL diversification in the chicken B cell line DT40. Here we show that immunoprecipitation of the BRCT domain of PARP-1 pulls down Ku70 and the DNA–PK complex although the BRCT domain of PARP-1 does not bind DNA, suggesting that this interaction is not DNA dependent. Through sequencing the IgL variable region in PARP-1−/− cells that also lack Ku70 or Lig4, we show that Ku70 or Lig4 deficiency restores GCV to PARP-1−/− cells and conclude that the mechanism by which PARP-1 is promoting mutagenic repair is by inhibiting high-fidelity repair which would otherwise be mediated by Ku70 and Lig4.

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The BRCT Domain of PARP-1 Is Required for Immunoglobulin Gene Conversion

Abstract: During affinity maturation, genomic integrity is maintained through specific targeting of DNA mutations. The DNA damage sensor PARP-1 helps determine whether a DNA lesion results in faithful or mutagenic repair.

Cited by 28 publications

References 40 publications

GANP Regulates the Choice of DNA Repair Pathway by DNA-PKcs Interaction in AID-Dependent IgV Region Diversification

GANP Regulates the Choice of DNA Repair Pathway by DNA-PKcs Interaction in AID-Dependent IgV Region Diversification

Poly(ADP-ribose) Polymerase 1 Is a Key Regulator of Estrogen Receptor α-dependent Gene Transcription

Competition between PARP-1 and Ku70 control the decision between high-fidelity and mutagenic DNA repair

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