6bcd
Crystal structure of Rev7-K44A/R124A/A135D in complex with Rev3-RBM2 (residues 1988-2014)
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) polymerases Polzeta and Rev1 form a complex that enables replication of damaged DNA. The Rev7 subunit of Polzeta, which is a multifaceted HORMA (Hop1, Rev7, Mad2) protein with roles in TLS, DNA repair, and cell-cycle control, facilitates assembly of this complex by binding Rev1 and the catalytic subunit of Polzeta, Rev3. Rev7 interacts with Rev3 by a mechanism conserved among HORMA proteins, whereby an open-to-closed transition locks the ligand underneath the "safety belt" loop. Dimerization of HORMA proteins promotes binding and release of this ligand, as exemplified by the Rev7 homolog, Mad2. Here, we investigate the dimerization of Rev7 when bound to the two Rev7-binding motifs (RBMs) in Rev3 by combining in vitro analyses of Rev7 structure and interactions with a functional assay in a Rev7(-/-) cell line. We demonstrate that Rev7 uses the conventional HORMA dimerization interface both to form a homodimer when tethered by the two RBMs in Rev3 and to heterodimerize with other HORMA domains, Mad2 and p31(comet) Structurally, the Rev7 dimer can bind only one copy of Rev1, revealing an unexpected Rev1/Polzeta architecture. In cells, mutation of the Rev7 dimer interface increases sensitivity to DNA damage. These results provide insights into the structure of the Rev1/Polzeta TLS assembly and highlight the function of Rev7 homo- and heterodimerization. Rev7 dimerization is important for assembly and function of the Rev1/Polzeta translesion synthesis complex.,Rizzo AA, Vassel FM, Chatterjee N, D'Souza S, Li Y, Hao B, Hemann MT, Walker GC, Korzhnev DM Proc Natl Acad Sci U S A. 2018 Aug 15. pii: 1801149115. doi:, 10.1073/pnas.1801149115. PMID:30111544[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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