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Interaction between the Rev1 C-Terminal Domain and the PolD3 Subunit of Pol? Suggests a Mechanism of Polymerase Exchange upon Rev1/Pol?-Dependent Translesion Synthesis.


ABSTRACT: Translesion synthesis (TLS) is a mutagenic branch of cellular DNA damage tolerance that enables bypass replication over DNA lesions carried out by specialized low-fidelity DNA polymerases. The replicative bypass of most types of DNA damage is performed in a two-step process of Rev1/Pol?-dependent TLS. In the first step, a Y-family TLS enzyme, typically Pol?, Pol?, or Pol?, inserts a nucleotide across a DNA lesion. In the second step, a four-subunit B-family DNA polymerase Pol? (Rev3/Rev7/PolD2/PolD3 complex) extends the distorted DNA primer-template. The coordinated action of error-prone TLS enzymes is regulated through their interactions with the two scaffold proteins, the sliding clamp PCNA and the TLS polymerase Rev1. Rev1 interactions with all other TLS enzymes are mediated by its C-terminal domain (Rev1-CT), which can simultaneously bind the Rev7 subunit of Pol? and Rev1-interacting regions (RIRs) from Pol?, Pol?, or Pol?. In this work, we identified a previously unknown RIR motif in the C-terminal part of PolD3 subunit of Pol? whose interaction with the Rev1-CT is among the tightest mediated by RIR motifs. Three-dimensional structure of the Rev1-CT/PolD3-RIR complex determined by NMR spectroscopy revealed a structural basis for the relatively high affinity of this interaction. The unexpected discovery of PolD3-RIR motif suggests a mechanism of "inserter" to "extender" DNA polymerase switch upon Rev1/Pol?-dependent TLS, in which the PolD3-RIR binding to the Rev1-CT (i) helps displace the "inserter" Pol?, Pol?, or Pol? from its complex with Rev1, and (ii) facilitates assembly of the four-subunit "extender" Pol? through simultaneous interaction of Rev1-CT with Rev7 and PolD3 subunits.

SUBMITTER: Pustovalova Y 

PROVIDER: S-EPMC4898654 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Interaction between the Rev1 C-Terminal Domain and the PolD3 Subunit of Polζ Suggests a Mechanism of Polymerase Exchange upon Rev1/Polζ-Dependent Translesion Synthesis.

Pustovalova Yulia Y   Magalhães Mariana T Q MT   D'Souza Sanjay S   Rizzo Alessandro A AA   Korza George G   Walker Graham C GC   Korzhnev Dmitry M DM  

Biochemistry 20160324 13


Translesion synthesis (TLS) is a mutagenic branch of cellular DNA damage tolerance that enables bypass replication over DNA lesions carried out by specialized low-fidelity DNA polymerases. The replicative bypass of most types of DNA damage is performed in a two-step process of Rev1/Polζ-dependent TLS. In the first step, a Y-family TLS enzyme, typically Polη, Polι, or Polκ, inserts a nucleotide across a DNA lesion. In the second step, a four-subunit B-family DNA polymerase Polζ (Rev3/Rev7/PolD2/P  ...[more]

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