Recombination signal sequences

Recombination signal sequences are conserved sequences of noncoding DNA that are recognized by the RAG1/RAG2 enzyme complex during V(D)J recombination in immature B cells and T cells. Recombination signal sequences guide the enzyme complex to the V,D, and J gene segments that will undergo recombination during the formation of the heavy and light-chain variable regions in T-cell receptors and immunoglobulin molecules.

RSSs are made up of conserved heptamer sequences (7 base pairs), spacer sequences, and conserved nonamer sequences (9 base pairs) that are adjacent to the V, D and J sequences in the heavy-chain region of DNA and the V and J sequences in the light-chain DNA region. Spacer sequences are located between heptamer and nonamer sequences and exhibit base pair variety but are always either 12 base pairs or 23 base pairs long. Unlike spacer sequences, heptamer sequences are usually CACAGTG, and the first three nucleotides are highly conserved. Nonamers are usually ACAAAAACC, and the A/T basepairs are also highly conserved. The RAG1/RAG2 enzyme complex follows the 12-23 rule when joining V,D, and J segments, pairing 12-bp spacer RSSs to 23-bp spacer RSSs. This prevents two different genes coding for the same region from recombining (ex. V-V recombination). RSSs are located between V,D, and J segments of the germ-line DNA of maturing B and T lymphocytes and are permanently spliced out of the final Ig mRNA product after V(D)J recombination is complete.

The RAG1/RAG2 enzyme complex recognizes the heptamer sequences flanking the V and J coding regions and nicks their 5' end, releasing the intervening DNA between the V and J coding regions. In the heavy-chain coding region of DNA, the RAG1/RAG2 enzyme complex recognizes the RSSs flanking the D and J segments and brings them together, forming a loop containing intervening DNA. The RAG1/RAG2 complex then introduces a nick at the 5' end of the RSS heptamers adjacent to the coding regions on both the D and J segments, permanently removing the loop of intervening DNA and creating a double-stranded break that is repaired by VDJ recombinase enzymes. This process is repeated for the joining of V to DJ. In light-chain rearrangement, only V and J segments are brought together.

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