Identification of the Catalytic Subunit of DNA Dependent Protein Kinase as the Product of the Mouse scid Gene

Abstract

A severe combined immunodeficient (scid) mouse was identified by Bosma in 1983 (Bosma et al. 1983) and found to lack mature T and B cells. Subsequently, the immune deficiency of scid mice was determined to be due to an inability to undergo effective V(D)J recombination, a process which occurs during T and B cell development and effects the reassortment of the variable (V), diversity (D) and joining (J) segments into a contiguous and functional exon (Schuler et al. 1986; Lieber et al. 1988; Malynn et al. 1988; Blackwell et al. 1989; Bosma and Carroll 1991). In germ line cells, each V, D and J segment is associated with a partially conserved recombination signal sequence (RSS), and the first step in V(D)J recombination involves the introduction of two double strand breaks (dsbs) between two RSS and their associated V D or J coding sequences (for reviews, see Alt et al. 1992; Gellert 1992; Lewis 1994). The ends of these two dsbs are recombined to yield an RSS junction, which represents the precise joining of two RSS sequences, and a coding junction, at which two coding sequences are rejoined. In contrast to the RSS junctions, however, coding joint formation is invariably imprecise with small nucleotide deletions or additions at the junctions, which can arise by a number of different mechanisms. This imprecision in coding joint formation, coupled with the reassortment of the V D, or J segments, provide mechanisms responsible for the enormous diversity of the immune response.