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A dual role for Parp3 during immunoglobulin class switch recombination

© IGBMC

 

While being dispensable for somatic hypermutation (SHM), the DNA repair factor Parp3 plays a dual role during immunoglobulin class switch recombination (CSR). Parp3 promotes the repair of double stranded DNA breaks (DSBs) induced by AID through the non homologous end joining (NHEJ) pathway and protects the immunoglobulin heavy (IgH) chain locus from sustained AID-induced DNA damage by promoting the eviction of the mutagenic enzymatic activity of AID from chromatin.

Parp3 negatively regulates immunoglobulin class switch recombination.

Robert I(1), Gaudot L(1), Rogier M(1), Heyer V(1), Noll A(2), Dantzer F(2), Reina-San-Martin B(1).

PLoS Genet May 22, 2015


June 15, 2015

The team of Bernardo Reina-San-Martin at IGBMC revealed new control mechanisms operating during antibody diversification. They have shown that the DNA repair factor Parp3 plays a dual role during immunoglobulin class switch recombination (CSR).

Parp3 promotes the repair of physiological DNA double strand breaks inflicted at the immunoglobulin heavy chain (IgH) locus and it protects the locus against sustained DNA damage.

This work provides novel insight in the mechanisms underlying the efficient generation of protective antibodies and the maintenance of genomic stability.


These results are published in Plos Genetics May 22nd 2015.


 
The extraordinary diversification capacity of B cells.

The immune system produces a great variety of B cells, which secrete antibodies. These molecules are capable of recognizing a large array of invading pathogens. Despite the large repertoire of antibodies present in the body that can respond to an infection, these are not necessarily of sufficient quality to efficiently neutralize pathogens. Hence, during infections, B cells diversify the antibodies they produce by two mechanisms: somatic hypermutation (SHM) and class switch recombination (CSR). SHM mutates the regions encoding the antigen-binding site, generating high-affinity antibodies. CSR allows B cells to switch the class of antibody they produce (from IgM to IgA, IgG or IgE), providing novel effector functions. Together, SHM and CSR establish highly specific, pathogen-adapted and long-lasting protective antibody responses.


Making efficient antibodies: a risky business.

SHM and CSR are initiated by the recruitment of the activation-induced cytidine deaminase (AID) enzyme to immunoglobulin loci. Once recruited, AID induces DNA lesions that are processed into mutations during SHM or to double stranded DNA breaks (DSBs) during CSR. The latter, activate the DNA damage response and mobilize multiple DNA repair factors, including DNA damage sensors from the Poly(ADP)ribose Polymerase (Parp) family of proteins to promote efficient DNA repair and long-range recombination. Despite its fundamental role in triggering B cell receptor diversification, AID carries a significant oncogenic potential. While on-target lesions trigger antibody diversification, off-target lesions contribute to malignant B cell transformation by activating oncogenes and/or by inducing chromosomal translocations.


A dual role for Parp3 during immunoglobulin class switch recombination.

To gain insight into these mechanisms, the group from Bernardo Reina-San-Martin focused on Parp3, a member of the Parp family, which was recently implicated in DNA repair. They show that Parp3 plays a CSR-specific role and that it is dispensable for SHM. During CSR, Parp3 facilitates the repair of AID-induced DSBs through the non-homologous end joining (NHEJ) pathway and that Parp3 controls the level of AID present at the IgH locus. Therefore these mechanisms protect the locus from sustained AID-induced damage, reduce the risk of triggering illegitimate recombination and enforce the maintenance of genomic integrity.


Antibody diversification, vaccination and cancer.

These results help delineating how the critical balance between the physiological and pathological roles of AID activity is maintained. Understanding how B cells regulate the processes leading to highly specific and adapted antibody responses will have implications for the emergence of novel vaccination strategies. Additionally, shedding light on the mechanisms controlling the oncogenic potential of AID will have implications for our understanding of the initiation of B cell malignancies and cancer.


© IGBMC

While being dispensable for somatic hypermutation (SHM), the DNA repair factor Parp3 plays a dual role during immunoglobulin class switch recombination (CSR). Parp3 promotes the repair of double stranded DNA breaks (DSBs) induced by AID through the non homologous end joining (NHEJ) pathway and protects the immunoglobulin heavy (IgH) chain locus from sustained AID-induced DNA damage by promoting the eviction of the mutagenic enzymatic activity of AID from chromatin.

Imprimer Envoyer

Université de Strasbourg
INSERM
CNRS

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