Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity

Abstract

Inborn errors of immunity (IEI) are a collection of diseases resulting from genetic causes that impact the immune system through multiple mechanisms. Natural killer cell deficiency (NKD) is one such IEI where natural killer (NK) cells are the main immune lineage affected. Though rare, the deficiency of several genes has been described as underlying causes of NKD, including MCM4, GINS1, MCM10, and GINS4, all of which are involved in the eukaryotic CMG helicase. The CMG helicase is made up of CDC45 – MCM – GINS and accessory proteins including MCM10. The CMG helicase plays a critical role in DNA replication by unwinding the double helix and enabling access of polymerases to single-stranded DNA, and thus helicase proteins are active in any proliferating cell. Replication stress, DNA damage, and cell cycle arrest are among the cellular phenotypes attributed to loss of function variants in CMG helicase proteins. Despite the ubiquitous function of the CMG helicase, NK cells have an apparent susceptibility to the deficiency of helicase proteins. This review will examine the role of the CMG helicase in inborn errors of immunity through the lens of NKD and further discuss why natural killer cells can be so strongly affected by helicase deficiency.