The IgH Eμ -MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation
Year: 2022
Type: preprint
Abstract: Two scaffold/matrix attachment regions (5’- and 3’- MARs Eμ ) flank the intronic core enhancer (c Eμ ) within the immunoglobulin heavy chain locus ( IgH ). Besides their conservation in mice and humans, the physiological role of MARs Eμ is still unclear and their involvement in somatic hypermutation (SHM) has never been deeply evaluated. By analysing a mouse model devoid of MARs Eμ , we observed an inverted substitution pattern: SHM being decreased upstream from cEμ and increased downstream of it. Strikingly, the SHM defect induced by MARs Eμ -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 cEμ 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. Our study pointed out an unexpected “fence” function of MARs Eμ regions in limiting the error-prone repair machinery to the variable region of Ig gene loci.
Institutions: Centre National de la Recherche Scientifique, Inserm, University of Sussex, Contrôle de la Réponse Immune B et Lymphoproliférations, Université de Limoges, Hôpital Universitaire Dupuytren, The Graduate Center, CUNY, City University of New York, National Institutes of Health, National Institute on Aging
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Award: G4026383997
OpenAlex ID: W4292063716