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Molecular Dynamic Simulation Approach Provides Insights into the Tumorigenesis of the N Terminal Portion of the Retinoblastoma Protein
Author(s) -
Vag Pietro,
Shor Audrey,
Borysov Sergiy
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04077
Subject(s) - carcinogenesis , retinoblastoma , biology , helicase , dna , microbiology and biotechnology , cancer research , cancer , genetics , gene , rna
The Retinoblastoma (Rb) protein is a master regulator of fundamental biological processes, such as the cell cycle entry, DNA replication, and apoptosis. Its functional inactivation is strongly implicated in the development of cancer, including retinoblastoma, osteosarcoma, breast, and lung cancer. Here we analyzed structural organization of the N terminal portion of Rb (RbN), known to harbor familial tumorigenic in‐frame deletions of exons 4, 5, 7 and 9, and exert a direct inhibitory effect on CMG helicase and DNA polymerase α via a bipartite mechanism. By utilizing the Molecular Dynamic Simulations, we reconstructed these RbN variants to visualize how accessibility of the CMG helicase and DNA polymerase α inhibitory domains is altered in the Δ4, Δ5, Δ7, and Δ9 RbN mutants. Our RbN models further supported the proposed bipartite mechanism of DNA replication inhibition by RbN and highlighted key structural components of RbN’s inhibitory domains. Our results reinforced previous studies, and provided insights on how mutations within the RbN contribute to tumorigenesis.