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

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.

Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

“…Ensuing T-cell dependent positive selection in the GC based on antigen binding results in affinity maturation and the generation of long-lived plasma cells that secrete high affinity antibodies. Next to SHM, AID is also crucial for class switch recombination (CSR) as processing of AIDinstigated genomic uracils in the switch (S) regions of the immunoglobulin heavy chain (IGH) locus primarily results in the formation of DNA double-strand breaks (DSB) that are required for CSR [18,19]. Of interest, AID has been firmly implicated in the generation of recurrent chromosomal translocations and the acquisition of driver mutations in MM, implicating a GC origin for MM [20,21].…”

Germinal Center Cells Turning to the Dark Side: Neoplasms of B Cells, Follicular Helper T Cells, and Follicular Dendritic Cells

“…The GC response, beneficial for the host during immune responses against invading pathogens, may have a detrimental role, the development of malignancies. B cells inside GC reactions are mutating at much higher rates than in any other site in the body ( 17 ), these mutations might turn B cells into a dark side, B cell lymphomas. Except the relatively rare lymphoblastic and mantle-cell lymphoma subtypes, B cell non-Hodgkin lymphomas (B−NHLs)—including diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and Burkitt lymphoma (BL)—are derived from GC B cells.…”

Fam72acontrols the balance between error-prone and error-free DNA repair during antibody diversification

“… Abstract Efficient humoral responses rely on DNA damage, mutagenesis and error-prone DNA repair. B cell receptor diversification through somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by cytidine deamination in DNA mediated by activation induced cytidine deaminase (AID) 1 and by the subsequent excision of the resulting uracils by Uracil DNA glycosylase (UNG) and by mismatch repair (MMR) proteins 2–4 . Although uracils arising in DNA are faithfully repaired 2–7 , it is not known how these pathways are co-opted to generate mutations and double stranded DNA breaks (DSBs) in the context of SHM and CSR 2,4,8 .…”

“…Mechanistically, both SHM and CSR are triggered by activation induced cytidine deaminase (AID), an enzyme which deaminates cytosines into uracils in DNA 11 . AID-generated U:G mismatches are processed mainly by the base-excision repair (BER) enzyme uracil-DNA-glycosylase (UNG) 4,12 but also by mismatch repair (MMR) 13 proteins to introduce mutations or double-stranded DNA breaks (DSBs) during SHM and CSR, respectively 2–4 . During SHM, DNA replication over U:G mismatches generates transition mutations at G:C base pairs.…”

“…During CSR, cytidine deamination and DNA cleavage on opposite strands generate DSBs 10 , which are a necessary intermediates for recombination 3 . While uracils in DNA are usually faithfully repaired 2–7 , the mechanisms by which AID-induced uracils are instead processed in an error-prone way in the context of antibody diversification through SHM and CSR is largely unknown 2–4 .…”