a heptamer of seven conserved nucleotides, a spacer region of 12 or 23 basepairs in length, and a nonamer of nine conserved nucleotides. While the majority of RSSs vary in sequence, the consensus heptamer and nonamer sequences are CACAGTG and ACAAAAACC, respectively; and although the sequence of the spacer region is poorly conserved, the length is highly conserved. The length of the spacer region corresponds to approximately one (12 basepairs) or two turns (23 basepairs) of the DNA helix. Following what is known as the 12/23 Rule, gene segments to be recombined are usually adjacent to RSSs of different spacer lengths (i.e., one has a "12RSS" and one has a "23RSS"). This is an important feature in the regulation of V(D)J recombination. Process V(D)J recombination begins when V(D)J recombinase (through the activity of RAG1) binds a RSS flanking a coding gene segment (V, D, or J) and creates a single-strand nick in the DNA between the first base of the RSS (just before the heptamer) and the coding segment. This is essentially energetically neutral (no need for ATP hydrolysis) and results in the formation of a free 3' hydroxyl group and a 5' phosphate group on the same strand. The reactive hydroxyl group is positioned by the recombinase to attack the phosphodiester bond of opposite strand, forming two DNA ends: a hairpin (stem-loop) on the coding segment and a blunt end on the signal segment. The current model is that DNA nicking and hairpin formation occurs on both strands simultaneously (or nearly so) in a complex known as a recombination center. The blunt signal ends are flush ligated together to form a circular piece of DNA containing all of the intervening sequences between the coding segments known as a signal joint (although circular in nature, this is not to be confused with a plasmid). While originally thought to be lost during successive cell divisions, there is evidence that signal joints may re-enter the genome and lead to pathologies by activating oncogenes or interrupting tumor suppressor gene function(s)[Ref]. The coding ends are processed further prior to their ligation by several events that ultimately lead to junctional diversity. Processing begins when DNA-PK binds to each broken DNA end and recruits several other proteins including Artemis, XRCC4, DNA ligase IV, Cernunnos, and several DNA polymerases. DNA-PK forms a complex that leads to its autophosphorylation, resulting in activation of Artemis. The coding end hairpins