Talk abstracts

Talk on Saturday 12:20-12:40pm submitted by Thomas Leeper

Molecular recognition of the SRA epigenetic regulatory lncRNA examined by NMR.

Thomas Leeper (University of Akron), Joel Caporoso (University of Akron), Daniel Morris (University of Akron), Caroline Davis (University of Akron), Stephanie Bilinovich (University of Akron)

Abstract:
The long-non-coding Steroid Receptor Activator RNA (SRA lncRNA) is part of a SRC-1 enzyme complex that acetylates histones.¹ This complex permits the transition of chromatin regions from silenced heterochromatin to expressed euchromatin.^2,3 The SRC-1/SRA complex enhances the expression of genes controlled by steroid nuclear receptors.^4,5,6 SRA1 RNA also interacts with many proteins, DDX17,⁶ SHARP,⁷ and others.⁸ Nuclear receptors are known to stimulate certain cancers; interestingly SRA RNA is dramatically overexpressed in, and stimulatory to, tumor cells.⁹ The SRA lncRNA facilitates chromatin remodeling as a non-coding RNA rather than as an mRNA. However, SRA is alternatively spliced into an mRNA encoding the SRA1p protein.¹⁰ Thus the gene for SRA is considered both an mRNA and lncRNA coding gene. SRA1p, along with SLIRP and SHARP, are repressors of SRA action and thus important checks on differentiation¹¹ and tumorigenesis. There are no structures of these proteins bound to RNA and the evidence for direct interactions is based on immunoprecipitation. Our NMR structure of the c-terminal domain of hSRA1p, previously thought to be an RRM domain, demonstrates that it is not an RRM nor does it have apparent SRA RNA binding activity. In contrast, RRM domains from SHARP and SLIRP are clearly identifiable and our progress towards the NMR structures of these RNP complexes will be presented.

References:
1. Lanz RB, et al. Tsai SY, Tsai MJ, O Malley BW (1999) Cell 97: 17-27.
2. Onate SA, et al. (1995) Science 270: 1354–7.
3. Onate SA, et al. Edwards DP, O Malley BW (1998) JBC 273: 12101–8.
4. Alen P, et al. (1999) MCB 19: 6085–97.
5. Aarnisalo P, et al. (1998) PNAS 95: 2122–7.
6. Watanabe M, et al. (2001) EMBO J. 20: 1341–52.
7. Shi Y, et al. (2001) Genes Dev. 15: 1140–51.
8. Colley SM, Leedman PJ (2011) Biochimie 93:1966-72.
9. Lanz RB, et al. (2003) MCB 23: 7163-76.
10. Chooniedass-Kothari S, et al. (2004) FEBS Lett. 566: 43–7.
11. Hubé F, et al. (2011) NAR 39: 513-25.

Keywords: NMR, lncRNA, epigenetics