Alexei V. Tulin, PhD
Office Phone: 215-728-7408
Developmentally regulated gene expression in multicellular eukaryotes requires the formation of dynamic tissue-specific chromatin structures that participate in activating certain genes and silencing others (Wolffe, Essays Biochem. 37:45, 2001). Furthermore, during an organism’s lifetime the established pattern of chromatin needs to be quickly reprogrammed in a response to environmental or hormonal signals (Thummel, Insect Biochem. Mol. Biol. 32:113, 2002). It has become increasingly clear that key aspects of chromatin structure and gene transcriptional activity are determined by a specific modification of histones (Elgin and Workman, Curr Opin Genet Dev. 12: 127, 2002; Fischle et al., Nature. 425:475, 2003).
Despite this exciting progress there remains much to be learned about how chromatin is programmed and how active or inactive domains are maintained. Our studies of the abundant nuclear enzyme poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) demonstrated that it plays novel and previously unknown roles in many of these processes. Distributed evenly along chromatin PARP is responsible for rapid local chromatin decondensation (loosening), which is required for transcriptional activation of many genes within particular chromatin blocks. Previously we have demonstrated that poly(ADP-ribosyl)ation is also involved in heterochromatin formation, the initiation and maintenance of nucleoli and telomere metabolism. The presence of several PARP-related proteins in mammals complicates the analysis and interpretation of results. Fortunately, only a single PARP gene is present in the Drosophila genome, making this animal an invaluable model system to study PARP function. Using Drosophila we study the molecular mechanisms of PARP activation, its action on chromatin and the interaction of PARP with other components of the chromatin remodeling machinery and transcriptional apparatus.Description of research projects
- Thomas CJ, Kotova E, Andrake M, Adolf-Bryfogle J, Glaser R, Regnard C, Tulin AV. 2014. Kinase-mediated changes in nucleosome conformation trigger chromatin decondensation via poly-ADP-ribosylation. Mol Cell. 53: 831–842.
- Lodhi N, Kossenkov A, Tulin AV. 2014. Bookmarking promoters in mitotic chromatin: Poly(ADP-ribose)Polymerase-1 as an epigenetic mark. Nucleic Acids Res. 42(11): 7028-7038.
- Thomas C, Tulin AV. 2013. Poly-ADP-Ribose Polymerase: Machinery for Nuclear Processes. Mol Aspects Med. 34(6): 1124-1137.
- Ji Y, Tulin AV. Poly(ADP-ribose) controls DE-cadherin-dependent stem cell maintenance and oocyte localization. Nat Commun. 2012 Mar 27;3:760. doi: 10.1038/ncomms1759. PubMed
- Boamah EK, Kotova E, Garabedian M, Jarnik M, Tulin AV. 2012. Poly(ADP-ribose) Polymerase 1 (PARP-1) regulates ribosomal biogenesis in Drosophila nucleoli. PLoS Genetics. 8(1):e1002442.
- Tulin A. Re-evaluating PARP1 inhibitor in cancer. Nat Biotechnol. 2011. 29(12):1078-9. PubMed
- Kotova E, Lodhi N, Jarnik M, Pinnola AD, Ji Y, Tulin AV. Drosophila histone H2A variant (H2Av) controls Poly(ADP-Ribose) Polymerase 1 (PARP1) activation in chromatin. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6205-10. PubMed
- Kotova E, Jarnik M, Tulin AV. Uncoupling of the trans-activation and trans-repression functions of PARP1 protein. Proc Natl Acad Sci U S A. 2010;107(14):6406-11. PubMed
- Ji Y, Tulin AV. Poly(ADP-ribosyl)ation of Heterogeneous Nuclear Ribonucleoproteins Modulates Splicing. Nucl. Acids Research. 2009;37:3501-13. PubMed
- Kotova E, Jarnik M, Tulin AV. Poly (ADP-ribose) Polymerase 1 is required for protein localization to Cajal body. PLoS Genetics. 2009;5(2):e1000387. PubMed
- Pinnola AD, Naumova N, Shah M, Tulin AV. Nucleosomal core histones mediate dynamic regulation of PARP1 protein binding to chromatin and induction of PARP1 enzymatic activity. J Biol Chem. 2007;282:32511-9. PubMed
- Tulin A, Spradling A. Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science. 2003;299(5606):560-2. PubMed
- Tulin A, Stewart D, Spradling AC. The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev. 2002;16(16):2108-19. PubMed