DNA-PKcs deficiency in human: long predicted, finally found

Abstract

DNA-PKcs is a key player in the nonhomologous end joining (NHEJ) pathway of DNA double strand break repair. Correct V(D)J recombination of T cell receptor and immunoglobulin genes is fully dependent on NHEJ, as it is involved in the formation of coding and signal joints. Therefore, a NHEJ defect results in absence of T and B cells. The DNA-PKcs deficient patient presented as a classical SCID patient, not different from a recombination activating gene or Artemis deficiency. The mutation concerned a hypomorphic missense mutation (L3062R) that did not result in absence of protein expression nor in deficient in vivo or in vitro (auto)phosphorylation. Although mutated DNA-PKcs was still able to recruit Artemis to the site of DNA damage, it was probably defective in Artemis activation. In the spontaneous animal models, however, the kinase activity was completely lost, which is essentially different from the human mutation. This observation suggests that some aspects of the DNA-PKcs function are unique to humans.

The Ku heterodimer: Function in DNA repair and beyond

“…There are several characterized human disorders with various degree of SCID phenotype that have been linked to mutations in NHEJ factors, such as DNA Ligase IV, Artemis, and XLF, as well as the other DSB repair pathway and DDR factors [197][198][199][200]. Interestingly, only a few individuals have been reported to have genetic defects in the DNA-PK complex, however, all presented mutations occurred in the DNA-PK CS subunit, and thus far, no disorder linked to Ku mutations has been identified [201,202]. It is currently unknown whether mutations in Ku are better tolerated in humans, or in the contrary, whether deleterious Ku mutations are lethal in humans.…”

Murine Prkdc Polymorphisms Impact DNA-PKcs Function

“…Decreased DNA-PKcs kinase activity has also been linked to individuals with lung cancer (4). Most recently, a Prkdc mutation was found in a human patient that exhibited a severe combined immune-deficient (SCID) phenotype (5). These and other studies suggest that SNPs in DNA repair genes such as Prkdc have the potential to affect cancer predisposition in the human population.…”

Repair of Double-Strand Breaks by End Joining

“…Impairment of c-NHEJ proteins confers profound cellular sensitivity to IR and other DSBinducing agents. Mouse models and genetic diseases, including DNA-PKcs, XLF, and Artemis mutations in humans, further show that c-NHEJ dysfunction leads to immunodeficiency and B-and T-cell loss due to failed V(D)J recombination as well as varying degrees of dysmorphology, growth retardation, and developmental delay that correlate with the degree of c-NHEJ dysfunction Moshous et al 2001;Buck et al 2006;Li et al 2008a;Kerzendorfer and O'Driscoll 2009;van der Burg et al 2009). One notable case is the ligase IV syndrome caused by hypomorphic mutations in Lig4 (Chistiakov 2010), which, like mouse models Rucci et al 2010), suggests that complete loss of this obligatory and specific c-NHEJ factor is incompatible with mammalian life.…”