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DNA damage response (DDR) and autophagy are concerned with maintaining cellular homeostasis and dysregulation of these two pathways lead to pathologic conditions including tumorigenesis. Autophagy is activated as a protective mechanism during DDR which is indicative of their functional cooperativity but the molecular mechanism leading to the convergence of these two pathways during genotoxic stress remains elusive. In this study, through in silico analysis, we have shown an interaction between the Mediator of DNA damage checkpoint 1 (MDC1), an important DDR-associated protein, and Beclin-1, an autophagy inducer. MDC1 is an adaptor or scaffold protein known to regulate DDR, apoptosis, and cell cycle progression. While, Beclin-1 is involved in autophagosome nucleation and exhibits affinity for binding to Fork-head-associated domain (FHA) containing proteins. The FHA domain is commonly conserved in DDR-related proteins including MDC1. Through molecular docking, we have predicted the modeled complex between the MDC1 FHA domain and the Beclin-1 Coiled coil domain (CCD). The docking complex was modeled using ClusPro2.0, based on the crystal structure for the dimerized MDC1 FHA domain and Beclin-1 CCD. The complex stability and binding affinities were assessed using a Ramachandran plot, MD simulation, MM/GBSA, and PRODIGY webserver. Finally, the hot-spot residues at the interface were determined using computational alanine scanning by the DrugScore PPI webserver. Our analysis unveils significant interaction between MDC1 and Beclin-1, involving hydrogen bonds, non-bonded contacts, and salt bridges and indicates MDC1 possibly recruits Beclin-1 to the DSBs, as a consequence of which Beclin-1 is able to modulate DDR.

Titel:	In silico study reveals unconventional interactions between MDC1 of DDR and Beclin-1 of autophagy.
Autor/in / Beteiligte Person:	Pandya, K ; Singh, N
Link:	View record at Springer (Volltext)
Zeitschrift:	Molecular diversity, Jg. 27 (2023-12-01), Heft 6, S. 2789-2802
Veröffentlichung:	Leiden, The Netherlands : ESCOM Science Publishers, c1995-, 2023
Medientyp:	academicJournal
ISSN:	1573-501X (electronic)
DOI:	10.1007/s11030-022-10579-2
Schlagwort:	Beclin-1 metabolism Trans-Activators chemistry Trans-Activators genetics Trans-Activators metabolism Adaptor Proteins, Signal Transducing metabolism Molecular Docking Simulation Autophagy Nuclear Proteins chemistry Nuclear Proteins genetics Nuclear Proteins metabolism Cell Cycle Proteins
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Mol Divers] 2023 Dec; Vol. 27 (6), pp. 2789-2802. <i>Date of Electronic Publication: </i>2022 Dec 08. MeSH Terms: Nuclear Proteins* / chemistry ; Nuclear Proteins* / genetics ; Nuclear Proteins* / metabolism ; Cell Cycle Proteins* ; Beclin-1 / metabolism ; Trans-Activators / chemistry ; Trans-Activators / genetics ; Trans-Activators / metabolism ; Adaptor Proteins, Signal Transducing / metabolism ; Molecular Docking Simulation ; Autophagy References: Ruff SE, Logan SK, Garabedian MJ, Huang TT (2020) Roles for MDC1 in cancer development and treatment. DNA Repair (Amst). https://doi.org/10.1016/j.dnarep.2020.102948. (PMID: 10.1016/j.dnarep.2020.10294832866776) ; Czarny P, Pawlowska E, Bialkowska-Warzecha J, Kaarniranta K, Blasiak J (2015) Autophagy in DNA damage response. Int J Mol Sci 16(2):2641–2662. https://doi.org/10.3390/ijms16022641. 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Contributed Indexing: Keywords: And tumor; Autophagy; Beclin-1; DNA damage response; Mediator of DNA damage checkpoint 1 Substance Nomenclature: 0 (Nuclear Proteins) ; 0 (Beclin-1) ; 0 (Cell Cycle Proteins) ; 0 (Trans-Activators) ; 0 (Adaptor Proteins, Signal Transducing) Entry Date(s): Date Created: 20221209 Date Completed: 20231113 Latest Revision: 20231113 Update Code: 20240513

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In silico study reveals unconventional interactions between MDC1 of DDR and Beclin-1 of autophagy.