6ve5
X-ray structure of human REV7 in complex with Shieldin3 (residues 41-74)
Structural highlights
FunctionMD2L2_HUMAN Adapter protein able to interact with different proteins and involved in different biological processes. Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis. Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions. May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1. Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle. Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe translesion synthesis (TLS) DNA polymerases Rev1 and Polzeta function together in DNA lesion bypass during DNA replication, acting as nucleotide inserter and extender polymerases, respectively. While the structural characterization of the Saccharomyces cerevisiae Polzeta in its DNA-bound state has illuminated how this enzyme synthesizes DNA, a mechanistic understanding of TLS also requires probing conformational changes associated with DNA- and Rev1 binding. Here, we used single-particle cryo-electron microscopy to determine the structure of the apo Polzeta holoenzyme. We show that compared with its DNA-bound state, apo Polzeta displays enhanced flexibility that correlates with concerted motions associated with expansion of the Polzeta DNA-binding channel upon DNA binding. We also identified a lysine residue that obstructs the DNA-binding channel in apo Polzeta, suggesting a gating mechanism. The Polzeta subunit Rev7 is a hub protein that directly binds Rev1 and is a component of several other protein complexes such as the shieldin DNA double-strand break repair complex. We analyzed the molecular interactions of budding yeast Rev7 in the context of Polzeta and those of human Rev7 in the context of shieldin using a crystal structure of Rev7 bound to a fragment of the shieldin-3 protein. Overall, our study provides new insights into Polzeta mechanism of action and the manner in which Rev7 recognizes partner proteins. Cryo-EM reveals conformational flexibility in apo DNA polymerase zeta.,Du Truong C, Craig TA, Cui G, Botuyan MV, Serkasevich RA, Chan KY, Mer G, Chiu PL, Kumar R J Biol Chem. 2021 Aug;297(2):100912. doi: 10.1016/j.jbc.2021.100912. Epub 2021 , Jun 24. PMID:34174285[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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