Base Excision Repair in the Immune System: Small DNA Lesions With Big Consequences.

Maria Stratigopoulou,Tijmen P Van Dam,Jeroen E J Guikema

doi:10.3389/fimmu.2020.01084

Maria Stratigopoulou, Tijmen P Van Dam + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2020.01084

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Abstract

The integrity of the genome is under constant threat of environmental and endogenous agents that cause DNA damage. Endogenous damage is particularly pervasive, occurring at an estimated rate of 10,000–30,000 per cell/per day, and mostly involves chemical DNA base lesions caused by oxidation, depurination, alkylation, and deamination. The base excision repair (BER) pathway is primary responsible for removing and repairing these small base lesions that would otherwise lead to mutations or DNA breaks during replication. Next to preventing DNA mutations and damage, the BER pathway is also involved in mutagenic processes in B cells during immunoglobulin (Ig) class switch recombination (CSR) and somatic hypermutation (SHM), which are instigated by uracil (U) lesions derived from activation-induced cytidine deaminase (AID) activity. BER is required for the processing of AID-induced lesions into DNA double strand breaks (DSB) that are required for CSR, and is of pivotal importance for determining the mutagenic outcome of uracil lesions during SHM. Although uracils are generally efficiently repaired by error-free BER, this process is surprisingly error-prone at the Ig loci in proliferating B cells. Breakdown of this high-fidelity process outside of the Ig loci has been linked to mutations observed in B-cell tumors and DNA breaks and chromosomal translocations in activated B cells. Next to its role in preventing cancer, BER has also been implicated in immune tolerance. Several defects in BER components have been associated with autoimmune diseases, and animal models have shown that BER defects can cause autoimmunity in a B-cell intrinsic and extrinsic fashion. In this review we discuss the contribution of BER to genomic integrity in the context of immune receptor diversification, cancer and autoimmune diseases.

Highlights

The adaptive immune response is of crucial importance for the elimination of pathogens, such as bacteria, viruses, and other foreign substances
Loss of Methyl-CpG Binding Domain Protein 4 (MBD4) resulted in a significant increase in somatic hypermutation (SHM), mostly focused at C/G bases, but to a much lesser extent than in Uracil DNA Glycosylase (UNG) deficient DT40 cells [130]. These results suggest that MBD4 is involved in U removal during SHM and perhaps during class switch recombination (CSR), but has a less prominent function than UNG, it must be noted that these studies were conducted in DT40 cells overexpressing activation-induced cytidine deaminase (AID), which may have amplified the observed effects
Based on our findings we propose that AID/UNG/AP Endonuclease 1 (APE1)-generated nicks are shunted toward errorprone repair by the non-canonical MMR (ncMMR) system, as POLB is limiting in germinal centers (GC) B cells, thereby bypassing base excision repair (BER) and nick-sealing by LIG3

Summary

Introduction

The adaptive immune response is of crucial importance for the elimination of pathogens, such as bacteria, viruses, and other foreign substances. It was shown that the endonuclease activity of PMS2 is responsible for the residual A:T mutagenesis in UNG and SMUG1 deficient B cells, but whether loss of PMS2 further diminishes A:T mutations in Ung−/− Smug1−/− mice remains to be tested [69].

Results

Conclusion