Formation of hMSH4–hMSH5 heterocomplex is a prerequisite for subsequent GPS2 recruitment

Lee, Tai-Hsien; Yi, Wei; Griswold, Michael D.; Zhu, Fengxue; Her, Chengtao

doi:10.1016/j.dnarep.2005.07.004

Cited by 31 publications

(45 citation statements)

References 28 publications

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“…The 293T/f-hMSH5 and 293T/ f45 cell lines were described previously (18,19). Cells were maintained in DMEM containing 10% fetal bovine serum (Biomeda, Foster City, CA) and 10 Ag/mL blasticidin (Invitrogen, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Physical and Functional Interaction between hMSH5 and c-Abl

Lee

Tompkins

et al. 2006

Cancer Research

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Despite being a member of the mismatch repair family of proteins, the biological functions of hMSH5 in human cells are presently elusive. Here, we report a novel physical and functional interaction between hMSH5 and c-Abl; the latter is a critical non-receptor tyrosine kinase involved in many critical cellular functions including DNA damage response, in which the kinase activity is normally suppressed in the absence of biological challenges. Our data indicate that hMSH5 associates with c-Abl in vivo, which is mediated by a direct physical interaction between the NH 2 terminus (residues 1-109) of hMSH5 and the c-Abl SH3 domain. This physical interaction facilitates the activation of c-Abl tyrosine kinase and the phosphorylation of hMSH5 in response to ionizing radiation. Our data also indicate that the hMSH5 P29S variant overactivates the c-Abl tyrosine kinase activity. Furthermore, it seems that the tyrosine phosphorylation of hMSH5 promotes the dissociation of hMSH4-hMSH5 heterocomplex. Together, the revealed physical and functional interaction of hMSH5 with c-Abl implies that the interplay between hMSH5 and c-Abl could manipulate cellular responses to ionizing radiation-induced DNA damages. (Cancer Res 2006; 66(1): 151-8)

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Section: Methodsmentioning

confidence: 99%

Physical and Functional Interaction between hMSH5 and c-Abl

Lee

Tompkins

et al. 2006

Cancer Research

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“…GPS2 and TBL1 interact with the conserved core region of SMRT and NCoR, which has been characterized as repression domain 1 (RD1) 26 . GPS2 has been reported to interact with a number of transcriptional regulators including P53, LXR, RFX4_v3, papilloma virus proteins E2 and E6 as well as the DNA repair proteins hMSH4/5 [27][28][29][30][31][32] . In several of these cases it appears that GPS2 plays a role in transcriptional activation, but the role of GPS2 in both activation and repression complexes is poorly understood.…”

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confidence: 99%

Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery

Oberoi

Fairall

Watson

et al. 2011

Nat Struct Mol Biol

140

156

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Eukaryotic transcriptional repressors function by recruiting large co-regulatory complexes that target histone deacetylase enzymes to gene promoters/enhancers. Transcriptional repression complexes, assembled by the co-repressor NCoR, and its homologue SMRT, play critical roles in many processes including development and metabolic physiology. The core repression complex involves the recruitment of three proteins: HDAC3, GPS2 and TBL1 to a highly conserved repression domain within SMRT and NCoR. We have used a variety of structural and functional approaches to gain insight into the assembly, stoichiometry and biological role of this complex. We report the crystal structure of the tetrameric oligomerization domain of TBL1, which interacts with both SMRT and GPS2, and the NMR structure of the interface complex between GPS2 and SMRT. These structures, together with computational docking, mutagenesis and functional assays, reveal the assembly mechanism and stoichiometry of the co-repressor complex.The regulated repression of transcription plays a key role in many biological processes. These include cell fate decisions during development and cellular differentiation, as well as the maintenance of homeostasis. SMRT and NCoR are large homologous co-repressor proteins that were identified through their role in transcriptional repression by many 5 Corresponding author: john.schwabe@le.ac.uk. 4 These authors should be considered co-first authors. Author ContributionsThe contributions of J.O., L.F. & P.W. were critical to the final manuscript and these authors should be considered co-first authors. J.O. (assisted by J.Gooch) performed most of the protein cloning, expression, purification and interaction mapping, although important preliminary experiments were performed by B.K. J.O. prepared the GPS2-SMRT complex for NMR structure determination which was carried out by J-C.Y. and D.N. Crystallizations were performed primarily by J.O., with some later trials by J.Greenwood and L.F. Crystal structure determinations were performed by L.F., J.O. and J.W.R.S. The interaction motifs in GPS2 and SMRT were identified by J.W.R.S. and tested by pull-down experiments by J.O. Fluorescence polarization, co-immunoprecipitation and co-transfection/ purification assays were performed by P.W. The two-hybrid assays, gel filtrations and NMR comparisons of WT and MT TBL1 were performed by P.W., Z.C. and B.G. In silico docking experiments were performed by T.K. The laboratories of L.N. and D.N. provided experimental expertise for transfection and NMR studies respectively. J.W.R.S. planned and supervised the project and prepared the manuscript with assistance from the other authors. Accession Codes1H, 13C and 15N NMR resonance assignments for the SMRT(167-207) -GPS2(53-90) complex have been deposited at the BioMagResBank under accession code 17271, and the coordinates have been deposited under the pdb accession code 215G. The TBL1 X-ray structures have been deposited with the PDB codes (2XTC, 2XTD & 2XTE). When purified from HeLa cell extr...

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“…A model for hMSH4-hMSH5 in meiotic recombination has been proposed (Snowden et al 2004), implicating their role in linking DSB repair to the regulation of crossover (CO) formation. It is known that the amino terminal region of hMSH4, composed of amino acid residues 148-387, is involved in mediating homotypic interaction (Her et al 1999;Lee et al 2006). Due to the physical separation of the hetero-and homo-interacting domains on hMSH4, it has been suggested that hMSH4 and hMSH5 may form a multimeric protein complex such as a tetramer.…”

Section: Structural Properties Of Msh4 and Msh5 Proteins 221 Generamentioning

confidence: 99%

“…Due to the physical separation of the hetero-and homo-interacting domains on hMSH4, it has been suggested that hMSH4 and hMSH5 may form a multimeric protein complex such as a tetramer. In addition, it has been demonstrated that the interface of hMSH4-hMSH5 heterocomplex forms a composite interaction domain for GPS2; the latter is a protein factor involved in intracellular signaling and DNA damage response (Jin et al 1997;Lee et al 2006;Peng et al 2001;Spain et al 1996). The interplay of GPS2 with the hMSH4-hMSH5 heterocomplex may provide a link to downstream molecular events required for Holliday junction processing and subsequent resolution.…”

Section: Structural Properties Of Msh4 and Msh5 Proteins 221 Generamentioning

confidence: 99%