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Mark G. Alexandrow
Academic Rank: Assistant Member
We study how the initiation of DNA replication is controlled, and plan to design novel cancer drugs that target proteins involved in this process.
- Molecular Oncology
- Thoracic Oncology
- Cancer Biology and Evolution Program
- Lung Cancer Center of Excellence
- Cancer Chemoprevention Research Interest Group
Education & Training
- Vanderbilt University, PhD - Department of Cell Biology
- University of Virginia School of Medicine, Fellow - Biochemistry and Molecular Genetics
- Vanderbilt University School of Medicine, Fellow
The research in Dr. Alexandrow's laboratory is focused on two central areas: (1) the mechanisms by which positive growth factor signals or inhibitory TGF-beta signals regulate the assembly and function of pre-(DNA) Replication Complexes (preRCs) in late G1 phase, and (2) how the DNA replication machinery and preRCs utilize chromatin remodeling complexes to gain access to the DNA substrate during late G1 and S-phase. The preRC is composed of multiple protein subunits that assemble in a stepwise and tightly regulated manner: Origin Recognition Complex (ORC), Cdc6, Cdt1, and the Mini-Chromosome Maintenance (MCM) helicase. After this forms, other proteins are recruited, including Cdc45, Mcm10, PCNA, and DNA polymerases. At G1/S, this complex is triggered and S-phase begins. However, very little is known in mammalian cells regarding how preRC assembly is regulated at the molecular level, how growth factors modulate preRC assembly, and how preRC activation is triggered at G1/S by cell cycle factors such as cyclin-dependent kinases. Furthermore, there is little knowledge of how the regulation of preRC assembly and activation is deregulated in cancer cells. Loss of control over MCM loading and activation is known to lead to re-replication within one cell cycle, producing genomic instability that contributes to tumorigenesis, and this concept provides a strong argument for understanding the molecular and biochemical events that govern preRC dynamics. The long term goal of this research is not only to understand the regulation of preRC function and assembly in late G1, but also to identify novel protein-protein interactions and key regulatory steps that might serve as useful targets for small molecule drug design/intervention for the treatment of cancer.
- Leone A, Diorio G, Sexton W, Schell M, Alexandrow M, Fahey JW, Kumar NB. Sulforaphane for the chemoprevention of bladder cancer: molecular mechanism targeted approach. Oncotarget. 2017 May;8(21):35412-35424. Pubmedid: 28423681. Pmcid: PMC5471065.
- Bryant VL, Elias RM, McCarthy SM, Yeatman TJ, Alexandrow MG. Suppression of Reserve MCM Complexes Chemosensitizes to Gemcitabine and 5-Fluorouracil. Mol Cancer Res. 2015 Sep;13(9):1296-1305. Pubmedid: 26063742. Pmcid: PMC4573356.
- Borysov SI, Nepon-Sixt BS, Alexandrow MG. The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas. Mol Cell Biol. 2015 Dec;36(5):832-845. Pubmedid: 26711265. Pmcid: PMC4760216.
- Borysov S, Bryant VL, Alexandrow MG. Analysis of DNA replication associated chromatin decondensation: in vivo assay for understanding chromatin remodeling mechanisms of selected proteins. Methods Mol Biol. 2015 Apr;1288:289-303. Pubmedid: 25827886.
- Kumar NB, Quinn GP, Alexandrow MG, Gray J, Schell M, Sutton S, Haura EB. Chemoprevention Trial Feasibility Using Botanicals in Exceptionally High Risk Populations for Lung Cancer. J Clin Trials. 2014 Sep;4(4). Pubmedid: 26101725. Pmcid: PMC4474484.
- Gray JE, Altiok S, Alexandrow MG, Walsh FW, Chen J, Schell MJ, Tai DF, Bepler G. Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers. Cancer. 2013 Mar;119(5):1023-1032. Pubmedid: 23065656. Pmcid: PMC3578040.
- Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB, Kumar NB. Curcumin: a novel Stat3 pathway inhibitor for chemoprevention of lung cancer. Eur J Cancer Prev. 2012 Sep;21(5):407-412. Pubmedid: 22156994. Pmcid: PMC3319490.
- Wong PG, Winter SL, Zaika E, Cao TV, Oguz U, Koomen JM, Hamlin JL, Alexandrow MG. Cdc45 limits replicon usage from a low density of preRCs in mammalian cells. PLoS One. 2011 Mar;6(3):e17533. Pubmedid: 21390258. Pmcid: PMC3046982.
- Wong PG, Glozak MA, Cao TV, Vaziri C, Seto E, Alexandrow M. Chromatin unfolding by Cdt1 regulates MCM loading via opposing functions of HBO1 and HDAC11-geminin. Cell Cycle. 2010 Nov;9(21):4351-4363. Pubmedid: 20980834. Pmcid: PMC3055186.
- Mukherjee P, Winter SL, Alexandrow MG. Cell cycle arrest by transforming growth factor beta1 near G1/S is mediated by acute abrogation of prereplication complex activation involving an Rb-MCM interaction. Mol Cell Biol. 2010 Feb;30(3):845-856. Pubmedid: 19948884. Pmcid: PMC2812244.
- Rizwani W, Alexandrow M, Chellappan S. Prohibitin physically interacts with MCM proteins and inhibits mammalian DNA replication. Cell Cycle. 2009 May;8(10):1621-1629. Pubmedid: 19377303. Pmcid: PMC2805263.
- Mukherjee P, Cao TV, Winter SL, Alexandrow MG. Mammalian MCM loading in late-G(1) coincides with Rb hyperphosphorylation and the transition to post-transcriptional control of progression into S-phase. PLoS One. 2009 Jun;4(5):e5462. Pubmedid: 19421323. Pmcid: PMC2674209.
- Winter SL, Wong P, Alexandrow MG. In vivo chromatin decondensation assays: molecular genetic analysis of chromatin unfolding characteristics of selected proteins. Methods Mol Biol. 2009 Apr;523:27-40. Pubmedid: 19381923.
- Li CG, Gruidl M, Eschrich S, McCarthy S, Wang HG, Alexandrow MG, Yeatman TJ. Insig2 is associated with colon tumorigenesis and inhibits Bax-mediated apoptosis. Int J Cancer. 2008 Jul;123(2):273-282. Pubmedid: 18464289. Pmcid: PMC2650850.
- Liu P, Barkley LR, Day T, Bi X, Slater DM, Alexandrow MG, Nasheuer HP, Vaziri C. The Chk1-mediated S-phase checkpoint targets initiation factor Cdc45 via a Cdc25A/Cdk2-independent mechanism. J Biol Chem. 2006 Oct;281(41):30631-30644. Pubmedid: 16912045.
- Alexandrow MG, Hamlin JL. Chromatin decondensation in S-phase involves recruitment of Cdk2 by Cdc45 and histone H1 phosphorylation. J Cell Biol. 2005 Mar;168(6):875-886. Pubmedid: 15753125. Pmcid: PMC2171796.
- Alexandrow MG, Hamlin JL. Cdc6 chromatin affinity is unaffected by serine-54 phosphorylation, S-phase progression, and overexpression of cyclin A. Mol Cell Biol. 2004 Feb;24(4):1614-1627. Pubmedid: 14749377. Pmcid: PMC344196.
- Alexandrow MG, Ritzi M, Pemov A, Hamlin JL. A potential role for mini-chromosome maintenance (MCM) proteins in initiation at the dihydrofolate reductase replication origin. J Biol Chem. 2002 Jan;277(4):2702-2708. Pubmedid: 11723123.
- Alexandrow MG, Moses HL. c-myc-enhanced S phase entry in keratinocytes is associated with positive and negative effects on cyclin-dependent kinases. J Cell Biochem. 1998 Sep;70(4):528-542. Pubmedid: 9712150.