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

ABSTRACT:

Intoduction

Two scaffold/matrix attachment regions (5'- and 3'-MARs_Eµ ) flank the intronic core enhancer (cEµ) 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.

Methods

Our study analyzed SHM and its transcriptional control in a mouse model devoid of MARs_Eµ , further combined to relevant models deficient for base excision repair and mismatch repair.

Results

We observed an inverted substitution pattern in of MARs_Eµ -deficient animals: 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.

Discussion

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.

SUBMITTER: Martin OA 

PROVIDER: S-EPMC9971809 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature