Kenan Distinguished Professor of Biochemistry & Biophysics, UNC-CH
PHD - Duke University
Regulation of Gene Activity
My research interests are focused on the regulation of gene activity in animal cells, in particular regulation of gene expression during the cell cycle by postranscriptional mechanisms. One system we study is the regulation of histone mRNA, both during the mammalian cell cycle and during early development in frogs and sea urchins. Histone mRNAs are the only mRNAs which do not have poly(A)+ tails, ending instead in a conserved stem-loop structure. Histone mRNAs are present only in S-phase cells and most of the regulation is mediated by the 3' end of histone mRNA. Histone genes lack introns, and histone mRNA is formed by a single processing reaction, cleavage form the 3' end of the histone mRNA. The mRNA is then immediately transported to the cytoplasm. Both the cleavage reaction to form histone mRNA and the half-life of the histone mRNA are regulated during the cell cycle. We have cloned the cDNA for the stem-loop binding protein (SLBP) that binds the 3' end of histone mRNA and participates in all aspects of histone mRNA metabolism. SLBP is a critical factor involved in regulating histone mRNA levels. Our current interests are in understanding how SLBP carries out its multiple functions; RNA binding, 3' processing, transport, stimulator of translation and regulating histone mRNA half-life. In addition, we are studying how SLBP itself is regulated and how this regulation connects the other cell cycle regulators with the regulation of histone mRNA.
In embryos, which undergo a very rapid series of cell divisions after fertilization, there is an exponentially increasing demand for histones to assemble the newly replicated DNA into chromatin. During this time the histone mRNAs are not cell-cycle regulated but are stable for multiple cell cycles. We have cloned embryo specific SLBPs from these stages and are determining how they function to regulate histone mRNA metabolism in frog and sea urchin embryos. We are also studying the role of the G1 cyclins, cyclin D and cyclin E in the regulation of these early cell cycles which lack gap phases.
- Lane,K.R., Yu,Y., Lackey,P.E., Chen,X., Marzluff,W.F., and Cook,J.G. Cell cycle-regulated protein abundance changes in synchronously proliferating HeLa cells include regulation of pre-mRNA splicing proteins. 2013, PLOS ONE 8, e58456.
- Salzler,H.R.*, Tatomer,D.C.*, Malek,P.Y., McDaniel,S.L., Orlando,A.N., Marzluff,W.F., and Duronio,R.J. A sequence in the Drosophila H3-H4 promoter triggers histone locus body assembly and biosynthesis of replication-coupled histone mRNAs. Developmental Cell 24, 2013, 623-634.
- Su,W., Slepenkov,S.V., Slevin,M.K., Lyons,S.M., Ziemniak,M., Kowalska,J., Darzynkiewicz,E., Jemielity,J., Marzluff,W.F., and Rhoads,R.E. mRNAs containing the histone 3' stem-loop are degraded primarily by decapping mediated by oligouridylation of the 3' end. RNA 2013, 19, 1-16.
- Tan,D., Marzluff,W.F., Dominski,Z., and Tong,L. Structure of histone mRNA stem-loop, human stem-loop binding protein, and 3'hExo ternary complex. Science 2013, 339, 318-321.
- Yang,X.C., Sabath,I., Debski,J., Kaus-Drobek,M., Dadlez,M., Marzluff,W.F., and Dominski,Z. A Complex Containing the CPSF73 Endonuclease and Other Polyadenylation Factors Associates with U7 snRNP and Is Recruited to Histone Pre-mRNA for 3'-End Processing. Mol. Cell Biol. 2013, 33, 28-37.
- Jeck,W.R., Sorrentino,J.A., Wang,K., Slevin,M.K., Burd,C.E., Liu,J., Marzluff,W.F., and Sharpless,N.E. (Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19, 2013, 141-157.
- Lampson,B.L., Pershing,N.L., Prinz,J.A., Lacsina,J.R., Marzluff,W.F., Nicchitta,C.V., Macalpine,D.M., and Counter,C.M. Rare Codons Regulate KRas Oncogenesis. Curr. Biol. 2013, 23, 70-75.
- Krishnan,N., Lam,T.T., Fritz,A., Rempinski,D., O' Loughlin,K., Minderman,H., Berezney,R., Marzluff,W.F., and Thapar,R. The prolyl isomerase Pin1 targets SLBP to dissociate the SLBP-histone mRNA complex linking histone mRNA decay with SLBP ubiquitination. Mol. Cell Biol. 2012, 32, 4306-4322.
- Chen,J., Ezzeddine,N., Waltenspiel,B., Albrecht,T.R., Warren,W.D., Marzluff,W.F., and Wagner,E.J. An RNAi screen identifies additional members of the Drosophila Integrator complex and a requirement for cyclin C/Cdk8 in snRNA 3'-end formation. RNA 18, 2012, 2148-2156
- Martin,L., Meier,M., Lyons,S.M., Sit,R.V., Marzluff,W.F., Quake,S.R., and Chang,H.Y. Systematic reconstruction of RNA functional motifs with high-throughput microfluidics. Nat. Methods 9, 2012, 1192-1194.
- Mullen TE, Marzluff WF. Degradation of histone mRNA requires oligouridylation followed by decapping and simultaneous degradation of the mRNA both 5' to 3' and 3' to 5'. Genes Dev. 2008 Jan 1;22(1):50-65
- Wagner EJ, Burch BD, Godfrey AC, Salzler HR, Duronio RJ, Marzluff WF. A genome-wide RNA interference screen reveals that variant histones are necessary for replication-dependent histone pre-mRNA processing. Mol Cell. 2007 Nov 30;28(4):692-9
- Cakmakci NG, Lerner RS, Wagner EJ, Zheng L, Marzluff WF. SLIP1, a factor required for activation of histone mRNA translation by the stem-loop binding protein. Mol Cell Biol. 2008 Feb;28(3):1182-94. Epub 2007
- Marzluff WF. U2 snRNP: not just for poly(A) mRNAs. Mol Cell. 2007 Nov 9;28(3):353-4.
- Dominski Z, Marzluff WF. Formation of the 3' end of histone mRNA: getting closer to the end. Gene. 2007 Jul 15;396(2):373-90. Epub 2007
- Schnackenberg BJ, Palazzo RE, Marzluff WF. Cyclin E/Cdk2 is required for sperm maturation, but not DNA replication, in early sea urchin embryos. Genesis. 2007 May;45(5):282-91
- White AE, Leslie ME, Calvi BR, Marzluff WF, Duronio RJ. Developmental and cell cycle regulation of the Drosophila histone locus body. Mol Biol Cell. 2007 Jul;18(7):2491-502. Epub 2007
- Kupsco JM, Wu MJ, Marzluff WF, Thapar R, Duronio RJ. Genetic and biochemical characterization of Drosophila Snipper: A promiscuous member of the metazoan 3'hExo/ERI-1 family of 3' to 5' exonucleases. RNA. 2006 Dec;12(12):2103-17. Epub 2006
- Fernandez-Guerra A, Aze A, Morales J, Mulner-Lorillon O, Cosson B, Cormier P, Bradham C, Adams N, Robertson AJ, Marzluff WF, Coffman JA, Genevière AM. The genomic repertoire for cell cycle control and DNA metabolism in S. purpuratus. Dev Biol. 2006 Dec 1;300(1):238-51. Epub 2006
- Marzluff WF, Sakallah S, Kelkar H. The sea urchin histone gene complement. Dev Biol. 2006 Dec 1;300(1):308-20. Epub 2006
- Townley-Tilson WH, Pendergrass SA, Marzluff WF, Whitfield ML. Genome-wide analysis of mRNAs bound to the histone stem-loop binding protein. RNA. 2006 Oct;12(10):1853-67. Epub 2006
- Wagner EJ, Marzluff WF. ZFP100, a component of the active U7 snRNP limiting for histone pre-mRNA processing, is required for entry into S phase. Mol Cell Biol. 2006 Sep;26(17):6702-12
- Yang XC, Purdy M, Marzluff WF, Dominski Z. Characterization of 3'hExo, a 3' exonuclease specifically interacting with the 3' end of histone mRNA. J Biol Chem. 2006 Oct 13;281(41):30447-54. Epub 2006
- Wang HX, Weerasinghe RR, Perdue TD, Cakmakci NG, Taylor JP, Marzluff WF, Jones AM. A Golgi-localized hexose transporter is involved in heterotrimeric G protein-mediated early development in Arabidopsis. Mol Biol Cell. 2006 Oct;17(10):4257-69. Epub 2006
- Richardson RT, Alekseev OM, Grossman G, Widgren EE, Thresher R, Wagner EJ, Sullivan KD, Marzluff WF, O'Rand MG. Nuclear autoantigenic sperm protein (NASP), a linker histone chaperone that is required for cell proliferation. J Biol Chem. 2006 Jul 28;281(30):21526-34. Epub 2006
- Wagner EJ, Ospina JK, Hu Y, Dundr M, Matera AG, Marzluff WF. Conserved zinc fingers mediate multiple functions of ZFP100, a U7snRNP associated protein. RNA. 2006 Jul;12(7):1206-18. Epub 2006
- Godfrey AC, Kupsco JM, Burch BD, Zimmerman RM, Dominski Z, Marzluff WF, Duronio RJ. U7 snRNA mutations in Drosophila block histone pre-mRNA processing and disrupt oogenesis. RNA. 2006 Mar;12(3):396-409
- Borchers CH, Thapar R, Petrotchenko EV, Torres MP, Speir JP, Easterling M, Dominski Z, Marzluff WF. Combined top-down and bottom-up proteomics identifies a phosphorylation site in stem-loop-binding proteins that contributes to high-affinity RNA binding. Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3094-9. Epub 2006
208 Fordham Hall
Campus Box # 7100
Chapel Hill, NC 27599