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发布于:2020-11-27 12:53:57  访问:1 次 回复:0 篇
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[7]["Compound H"
The specic requirement for the UBM and UBZ domains of TLS polymerases for survival after DNA damage and for damageinduced relocalization of TLS polymerases into foci in vivo, however, makes a tempting argument that the interaction between TLS polymerases and monoubiquitinated PCNA functions as a mechanism to stimulate a switch between a How Much Is Target Circle replicative polymerase and a TLS polymerase.Once the TLS polymerase is recruited to the site of the lesion, an exchange is thought to occur between the replicative polymerase and the incoming TLS polymerase. The details of this process, however, are not well characterized.For example, it is unclear if the replicative polymerase must exit the primer terminus before the TLS polymerase can be recruited or if the replicative polymerase somehow aids in this transaction. Following the handoff between the replicative and TLS polymerase on the primer terminus, the subsequent nucleotide insertion across and extension past the lesion may require the concerted action of two or more TLS polymerases. Accurate DNA synthesis can therefore resume and the replication fork again moves forward. Following bypass by TLS, the lesion would again be a substrate for removal by DNA repair mechanisms.The described mechanism likely has more layers of complexity in vivo given that monoubiquitinated PCNA persists for hours after the removal of UV damage in human cells. In this situation, the purpose of TLS is not to restart a stalled replication fork but rather to seal gaps that have resulted from the replication machinery repriming downstream of the blocking lesion, thereby leaving behind a ssDNA gap opposite the lesion.Alternatively, gaps containing lesions can be formed as a result of processing of closely spaced lesions on opposite DNA strands or by the processing of interstrand crosslinks.It would be expected that this ["X-Pando Pipe Joint Compound gaplling mechanism would be utilized primarily outside of S phase, during G or GM phases of the cell cycle.It could, however, also occur during the later stages of S phase.In the gaplling model, once the cell identies a need for lesion bypass, the TLS polymerase is presumably directed to the ssDNA gap.In this situation, handoffs with the replicative polymerase are not expected to contribute signicantly in the recruitment of the TLS polymerase but might come into play after the lesion is bypassed if the remaining gap after the lesion is large.More profound phenotypes may be detected only upon the simultaneous loss of multiple TLS polymerases.It has been suggested that transient association of several polymerases with the DNA lesion at the primer terminus may occur sequentially until the bestsuited polymerase is able to perform lesion bypass. In such models, specicity of TLS for bypass of a particular lesion is imparted by a passive trialanderror approach based on the inherent efciency of TLS polymerases opposite their cognate lesion.However, the many levels of regulatory controls and proteinprotein interactions discussed in this review likely constrain which DNA polymerases are able to access a given primer terminus in a particular biological context.Ultimately, for both models of TLS lesion bypass, the differential primertemplate afnities, processivities, and bypass activities of translesion polymerases may be the primary mechanism by which a particular DNA polymerase gains access to the DNA.
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