AUTHOR=Martin Ophélie A. , Thomas Morgane , Marquet Marie , Bruzeau Charlotte , Garot Armand , Brousse Mylène , Bender Sébastien , Carrion Claire , Choi Jee Eun , Vuong Bao Q. , Gearhart Patricia J. , Maul Robert W. , Le Noir Sandrine , Pinaud Eric 

TITLE=The IgH Eµ-MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1030813

DOI=10.3389/fimmu.2023.1030813

ISSN=1664-3224

ABSTRACT=<sec><title>Intoduction</title><p>Two scaffold/matrix attachment regions (5’- and 3’-<italic>MARs<sub>Eµ</sub></italic>) flank the intronic core enhancer (c<italic>Eµ</italic>) within the immunoglobulin heavy chain locus (<italic>IgH</italic>). Besides their conservation in mice and humans, the physiological role of <italic>MARs<sub>Eµ</sub></italic> is still unclear and their involvement in somatic hypermutation (SHM) has never been deeply evaluated.</p></sec><sec><title>Methods</title><p>Our study analyzed SHM and its transcriptional control in a mouse model devoid of <italic>MARs<sub>Eµ</sub></italic>, further combined to relevant models deficient for base excision repair and mismatch repair.</p></sec><sec><title>Results</title><p>We observed an inverted substitution pattern in of <italic>MARs<sub>Eµ</sub></italic>-deficient animals: SHM being decreased upstream from c<italic>Eµ</italic> and increased downstream of it. Strikingly, the SHM defect induced by <italic>MARs<sub>Eµ</sub></italic>-deletion was accompanied by an increase of sense transcription of the IgH V region, excluding a direct transcription-coupled effect. Interestingly, by breeding to DNA repair-deficient backgrounds, we showed that the SHM defect, observed upstream from c<italic>Eµ</italic> in this model, was not due to a decrease in AID deamination but rather the consequence of a defect in base excision repair-associated unfaithful repair process.</p></sec><sec><title>Discussion</title><p>Our study pointed out an unexpected “fence” function of <italic>MARs<sub>Eµ</sub></italic> regions in limiting the error-prone repair machinery to the variable region of Ig gene loci.</p></sec>