I am fascinated by the mechanisms via which trans-acting RNA-binding proteins regulate gene expression, both in terms of mRNA translation and mRNA turnover. In particular my interests lie in understanding how upstream intracellular signalling pathways modulate RNA-binding protein function to control gene expression. To this end I have studied the function of the AU-rich element-binding protein tristetraprolin, misregulation of which is implicated in chronic inflammatory disease and cancer, and its regulation by the p38 MAPK and ERK pathways and I am now studying mammalian mRNA translation factors of the PABP family. I have identified over 20 novel PABP1 post-translational modifications, including several lysine residues that are subject to alternative methylation or acetylation and which may confer regulated protein interaction specificity. Work is ongoing to characterise the roles of these modifications in modulating PABP1 function.
More recently I have undertaken the study of mammalian PABP function in vivo, with particular emphasis on the role of PABPs in ensuring reproductive health and competence.
Current research projects
- Contribution of the poly(A)-binding protein (PABP) family, central post-transcriptional regulators, to human reproductive health.
- Regulation of PABP function by post-translational modification.
- Identification of novel functions for PABPs in post-transcriptional control of gene expression.
- Mechanism of anti-inflammatory action of human alpha-defensins (collaboration with Dr Mohini Gray, Edinburgh).
- Brook M, Gray NK. (2012) The role of mammalian poly(A)-binding proteins in co-ordinating mRNA turnover. Biochem Soc Trans. 40(4):856-64.
- Friend K, Brook M, Bezirci FB, Sheets MD, Gray NK, Seli E. (2012) Embryonic poly(A)-binding protein (ePAB) phosphorylation is required for Xenopus oocyte maturation. Biochem J. Epub ahead of print
- Brook M, Smith RW, Gray NK. (2012) A Molecular Doorstop Ensures a Trickle through Translational Repression. Cell. 149:13-5.
- Brook M*, McCracken L, Reddington JP, Lu ZL, Morrice NA, Gray NK. (2012) The multifunctional poly(A)-binding protein (PABP) 1 is subject to extensive dynamic post-translational modification, which molecular modelling suggests plays an important role in co-ordinating its activities. Biochem J. 441:803-12.
- Gorgoni B, Richardson WA, Burgess HM, Anderson RC, Wilkie GS, Gautier P, Martins JP, Brook M, Sheets MD, Gray NK. (2011) Poly(A)-binding proteins are functionally distinct and have essential roles during vertebrate development. Proc Natl Acad Sci U S A. 108:7844-9.
- Smith RWP, Anderson RC, Smith JWS, Brook M, Gray NK. (2011) DAZAP1, an RNA-binding protein required for development and spermatogenesis, can regulate mRNA translation. RNA. 17:1282-95.
- Salaun C, MacDonald AI, Larralde O, Howard L, Burgess HM, Lochtie K, Brook M, Malik P, Gray NK, Graham SV. (2010) Poly(A)-binding protein 1 (PABP1) partially relocalises to the nucleus during HSV-1 infection in an ICP27-independent manner and does not inhibit virus replication. J. Virol. 84: 8539-48.
- Peirce MJ, Brook M, Morrice N, Snelgrove R, Begum S, Lanfrancotti A, Notley C, Hussell T, Cope AP, Wait R. (2010) Themis2/ICB1 is a signaling scaffold that selectively regulates macrophage Toll-like receptor signaling and cytokine production. PLoS One. 5:e11465.
- Coldwell MJ, Gray NK, Brook M*. (2010) Cytoplasmic mRNA: move it, use it or lose it! Biochem Soc Trans. 38(6):1495-9.
- Brook M, Smith JW, Gray NK. (2009) The DAZL and PABP families: RNA-binding proteins with interrelated roles in translational control in oocytes. Reproduction. 137:595-617.
- Brook M, Tchen CR, Santalucia T, McIlrath J, Arthur JS, Saklatvala J, Clark AR. (2006) Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol Cell Biol. 26:2408-18.
- Hitti E, Iakovleva T, Brook M, Deppenmeier S, Gruber AD, Radzioch D, Clark AR, Blackshear PJ, Kotlyarov A, Gaestel M. (2006) Mitogen-activated protein kinase-activated protein kinase 2 regulates tumour necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol Cell Biol. 26:2399-407.
- Tchen CR, Brook M, Saklatvala J, Clark AR. (2004) The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself. J Biol Chem. 279:32393-400.
- Mahtani KR, Brook M, Dean JL, Sully G, Saklatvala J, Clark AR. (2001) Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumour necrosis factor alpha mRNA stability. Mol Cell Biol. 21:6461-9.
- Lasa M, Brook M, Saklatvala J, Clark AR. (2001) Dexamethasone destabilizes cyclooxygenase-2 mRNA by inhibiting mitogen-activated protein kinase p38. Mol Cell Biol. 21:771-80.
- Brook M, Sully G, Clark AR, Saklatvala J. (2000) Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade. FEBS Lett. 483:57-61.
- Dean JL, Brook M, Clark AR, Saklatvala J. (1999) p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem. 274:264-9.
- Ridley SH, Dean JL, Sarsfield SJ, Brook M, Clark AR, Saklatvala J. (1998) A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA. FEBS Lett. 439:75-80.
* Corresponding author
Guillermina Girardi, Jane Norman, Mohini Gray
Jason Chin (MRC LMB, Cambridge), Graham Burton (CTR, University of Cambridge), Emre Seli (Yale, USA)
2010 Post-transcriptional control: mRNA translation, localisation and turnover. Edinburgh, UK.