After incorporation of random nucleotides by TdT during heav
After incorporation of random (R,S)-Anatabine by TdT during heavy-chain rearrangements, both TdT and pol λ may perform in trans polymerase activity (in unknown proportions), whereas synthesis of the complementary strand can only be achieved by pol λ using its gap-filling activity, which TdT lacks because of its Loop1 (Figure 4). In light-chain gene rearrangements Pol μ can perform not only template-independent, but also in trans polymerase and gap-filling activities (Figure 4).
Perspectives and conclusion Due to its ability to add random sequences to a DNA primer, TdT is an intrinsically ‘unpredictable’ polymerase (rather than a ‘misguided’ one ). This explains its tight regulation both in time and space, in order to restrict its use to V(D)J recombination. Here we suggest that not only its recruitment but also its gradual stop is programmed, by switching to a previously unsuspected templating mode across strand breaks after the addition of 4–5 random nucleotides. This would be due to the spatial constraints of the architecture of the whole NHEJ apparatus, a very active field in structural biology that achieved impressive progress recently, first for the structure of the ligation complex , and more recently for the structure of the huge loading complex of NHEJ [93••, 94••, 95••]. It is known that TdT interacts with Ku heterodimer through its BRCT domain, as does pol μ [13, 14]. If the interaction of the BRCT domain with Ku heterodimer could be mapped, then it would be possible to place the polX with respect to the DNA–PKcs–DNA complex and thereby to shed light on spatial constraints at work. On the evolutionary level it would be interesting to do it for both pol mu and TdT, so as to assess how similar are the positioning of TdT and pol μ in this integrated view of the NHEJ complex. From Figure 1, it appears that TdT has lost just the 5′ phosphate binding site of pol mu and that its Loop1 is of the same length, but with a different sequence. Regarding Loop1 and its vexing property of escaping structural characterization in pol mu, we expect that the structure of the TdT chimera containing Loop1 of pol mu will inform us on its conformation and also allow, eventually, a comparison with the LigD polymerase that performs NHEJ in bacteria.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
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