Lesion bypass during

DNA replication during lesion bypass in vivo. Science 2003 300 65. 

Fig. 5. Models for DNA polymerase switching during translesion synthesis. (A) Model for lesion bypass by a single TLS polymerase. (B) Model for lesion bypass by two TLS polymerases, wherein the first polymerase inserts a nucleotide opposite the damaged site and the second extends the aberrant primer terminus. (See Color Insert.)...

Fig. 10. Switches between replicative and specialized DNA polymerases during translesion synthesis, (a) Pol III holoenzyme is able to elongate a primer in the vicinity of a lesion provided its 3 -extremity is located four or more nucleoddes dovmstream from the lesion site. If the primer is shorter, the proofreading exonuclease that is associated with Pol III degrades the primer (Fuji and Fuchs, 2004). (b) Minimal conditions for robust Pol V-mediated TLS. Two cofactors are essential for efficient Pol V-mediated lesion bypass (i) a DNA substrate onto which the / clamp is stably loaded,...

C. Sivitches Between Replicative and Specialized DNA Polymerases During Lesion Bypass... 

Fig. 4. Possible role of mismatch repair in the cytotoxicity of cisplatin. A) During replicative bypass, a mismatch is incorporated across from the cisplatin-DNA adduct. This compound lesion is bound by the mismatch repair proteins, which cut the DNA on the strand opposite the platinum. Repair synthesis would reproduce the same mismatch, resulting in a futile cycle and possibly the accumulation of DNA strand breaks which would activate apoptosis. B) Alternatively, the mismatch repair complex can recognize the cisplatin-DNA adduct alone and generate a signal that triggers apoptosis.

Opposite the 3 T of a TT dimer, Pol is unable to insert a nucleotide in vitro, although it is active for translesion synthesis opposite the 5 T of the dimer. Thus, other translesion polymerases are required to bypass the 3 T of the TT dimer and other lesions for which Pol is inactive. During translesion synthesis, the active site... 

It appears that multiple mechanisms exist for translesion synthesis, due to the involvement of multiple bypass polymerases. In the simplest case, one polymerase inserts a nucleotide opposite the lesion, and then the same polymerase extends the synthesis from opposite the lesion. This constitutes the one-polymerase two-step mechanism (Figure 22.23). Examples of this mode of translesion synthesis include the bypass of a TT dimer by Polr and the bypass of a (-)-trans-anU-bcn/o a ]pyrene-A 2-dG by PoIk. In a more complex scheme, following nucleotide insertion opposite the lesion by one polymerase, subsequent extension synthesis is catalyzed by another polymerase. This constitutes the two-polymerase two-step mechanism (Figure 22.23). PolC is believed to be the major extension polymerase during translesion synthesis by the two-polymerase two-step mechanism. Additionally, PoIk and Polr may also catalyze extension synthesis during the bypass of some selected lesions. 

Figure 13.2 Comparison of bypass of abasic site analogs by different polymerases. Substrates containing the abasic analog THF can adopt at least two conformations during Dpo4-catalyzed bypass of the lesion, namely extrahelical (PDB ISON) and intrahelical (PDB 1S10) conformations. The intrahelical orientation represents what occurs following...

N.E., and Patel, D.J. (2006) Stepwise translocation of Dpo4 polymerase during error-free bypass of an oxoG lesion. PLoS Biol., 4, ell. 

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