DNA repair defects and inborn errors of immunity: why we need to fix what is broken

Abstract

DNA damage is part and parcel of the life of a cell and an organism. Cells respond to DNA damage by initiating DNA damage response (DDR) pathways that allow for removal of the damaged DNA and subsequent repair. At least five major pathways of DNA repair operate in humans – base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) and DNA double-strand break repair (DSB), which involves homologous recombination (HR) and non-homologous end-joining (NHEJ). This talk will focus on DNA DSB repair, which is most commonly used in the immune system. Genetic diversity, through VDJ recombination, class-switch recombination and somatic hypermutation are essential in T and B cells, and are managed by numerous DNA repair pathways, but most prominently DNA DSB repair. Genetic defects in genes associated with DNA DSB repair are associated with syndromic immunodeficiencies (e.g., ataxia telangiectasia, Nijmegen Breakage Snydrome) or radiosensitive forms of severe combined immunodeficiency (rs-SCID), e.g., Artemis SCID, DNA ligase IV defects, Cernunnos deficiency, DNA-PKcs defects among others. These conditions are collectively called XCIND (X-ray/radiation sensitivity, cancer susceptibility, immunodeficiency, neurological development defects). This talk will provide an overview of DNA DSB repair defects and discuss a new flow cytometry assay, which is used for the diagnosis of these disorders in the clinical laboratory.