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Associate Professor of Pharmacology and Cancer Biology
Director of Graduate Studies, Pharmacology
Duke University School of Medicine
Durham, NC 27710
Our laboratory is interested in understanding the mechanisms by which the molecular architecture of the chromosome regulates fundamental biological processes such as replication and transcription. Specifically, how are replication, transcription and chromatin modification coordinated on a genomic scale to maintain genomic stability? We are addressing this question by using genomic, computational and biochemical approaches in multiple model systems including Drosophila melanogaster, Saccharomyces cerevisiae, and mammalian cell culture.
DNA replication is an essential cell cycle event required for the timely and accurate duplication of chromosomes. Replication initiates at multiple sites (called origins of replication) distributed across each chromosome. The failure to properly regulate origin selection and activation may result in catastrophic genomic instability and potentially tumorigenesis. Origins of DNA replication are marked by the formation of multi-protein complex, called the pre-RC. Despite conservation of the proteins that comprise the pre-RC in all eukaryotes, very little is known about the sequence and chromatin features required for the selection and regulation of metazoan origins. We are using next-generation sequencing based approaches to comprehensively identify and survey the chromatin features associated with start sites of DNA replication.
Belsky JA, MacAlpine HK, Lubelsky Y, Hartemink AJ, MacAlpine DM. Genome-wide chromatin footprinting reveals changes in replication origin architecture induced by pre-RC assembly. Genes Dev. 2015 Jan 15;29(2):212-24. doi: 10.1101/gad.247924.114. PubMed PMID: 25593310; PubMed Central PMCID: PMC4298139.
Powell SK, MacAlpine HK, Prinz JA, Li Y, Belsky JA, MacAlpine DM. Dynamic loading and redistribution of the Mcm2-7 helicase complex through the cell cycle. EMBO J. 2015 Feb 12;34(4):531-43. doi: 10.15252/embj.201488307. Epub 2015 Jan 2. PubMed PMID: 25555795; PubMed Central PMCID: PMC4331006.
Ho JW, Jung YL, Liu T, Alver BH, Lee S, Ikegami K, Sohn KA, Minoda A, Tolstorukov MY, Appert A, Parker SC, Gu T, Kundaje A, Riddle NC, Bishop E, Egelhofer TA, Hu SS, Alekseyenko AA, Rechtsteiner A, Asker D, Belsky JA, Bowman SK, Chen QB, Chen RA, Day DS, Dong Y, Dose AC, Duan X, Epstein CB, Ercan S, Feingold EA, Ferrari F, Garrigues JM, Gehlenborg N, Good PJ, Haseley P, He D, Herrmann M, Hoffman MM, Jeffers TE, Kharchenko PV, Kolasinska-Zwierz P, Kotwaliwale CV, Kumar N, Langley SA, Larschan EN, Latorre I, Libbrecht MW, Lin X, Park R, Pazin MJ, Pham HN, Plachetka A, Qin B, Schwartz YB, Shoresh N, Stempor P, Vielle A, Wang C, Whittle CM, Xue H, Kingston RE, Kim JH, Bernstein BE, Dernburg AF, Pirrotta V, Kuroda MI, Noble WS, Tullius TD, Kellis M, MacAlpine DM, Strome S, Elgin SC, Liu XS, Lieb JD, Ahringer J, Karpen GH, Park PJ. Comparative analysis of metazoan chromatin organization. Nature. 2014 Aug 28;512(7515):449-52. doi: 10.1038/nature13415. PubMed PMID: 25164756; PubMed Central PMCID: PMC4227084.
Lubelsky Y, Prinz JA, DeNapoli L, Li Y, Belsky JA, MacAlpine DM. DNA replication and transcription programs respond to the same chromatin cues. Genome Res. 2014 Jul;24(7):1102-14. doi: 10.1101/gr.160010.113. PubMed PMID: 24985913; PubMed Central PMCID: PMC4079966.
Lampson BL, Pershing NL, Prinz JA, Lacsina JR, Marzluff WF, Nicchitta CV, MacAlpine DM, Counter CM. Rare codons regulate KRas oncogenesis. Curr Biol. 2013 Jan 7;23(1):70-5. doi: 10.1016/j.cub.2012.11.031. Epub 2012 Dec 13. PubMed PMID: 23246410; PubMed Central PMCID: PMC3567844.