Imperial College London

ProfessorPaulFreemont

Faculty of MedicineDepartment of Infectious Disease

Chair in Protein Crystallography
 
 
 
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Contact

 

+44 (0)20 7594 5327p.freemont

 
 
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Location

 

259Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

325 results found

Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honore N, Doubeikovsky A, Duprez E, Pandolfi PP, Puvion E, Freemont P, de The Het al., 2001, Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation, Journal of Experimental Medicine, Vol: 193, Pages: 1361-1371, ISSN: 0022-1007

Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PML nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) α expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (As2O3) restore them. PML is conjugated by the ubiquitin-related peptide SUMO-1, a process enhanced by As2O3 and proposed to target PML to the nuclear matrix. We demonstrate that As2O3 triggers the proteasome-dependent degradation of PML and PML/RARα and that this process requires a specific sumolation site in PML, K160. PML sumolation is dispensable for its As2O3-induced matrix targeting and formation of primary nuclear aggregates, but is required for the formation of secondary shell-like NBs. Interestingly, only these mature NBs harbor 11S proteasome components, which are further recruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only likely accounts for the failure of PML-K160R to be degraded. Therefore, studying the basis of As2O3-induced PML/RARα degradation we show that PML sumolation directly or indirectly promotes its catabolism, suggesting that mature NBs could be sites of intranuclear proteolysis and opening new insights into NB alterations found in viral infections or transformation.

Journal article

Dulic A, Bates PA, Zhang XD, Martin SR, Freemont PS, Lindahl T, Barnes DEet al., 2001, BRCT domain interactions in the heterodimeric DNA repair protein XRCC1-DNA ligase III, BIOCHEMISTRY, Vol: 40, Pages: 5906-5913, ISSN: 0006-2960

Journal article

Freemont PS, 2000, Ubiquitination: RING for destruction?, Current Biology, Vol: 10, ISSN: 0960-9822

Ubiquitination targets proteins for degradation and is a potent regulator of cellular protein function. Recent results implicate the RING finger domain in specific Ubiquitination events; it is possible that all RING proteins act as E3 ubiquitin protein ligases, with implications for a variety of biological areas. © 2000 Elsevier Science Ltd. All rights reserved.

Journal article

Zhang XD, Shaw A, Bates PA, Newman RH, Gowen B, Orlova E, Gorman MA, Kondo H, Dokurno P, Lally J, Leonard G, Meyer H, van Heel M, Freemont PSet al., 2000, Structure of the AAA ATPase p97, MOLECULAR CELL, Vol: 6, Pages: 1473-1484, ISSN: 1097-2765

Journal article

Linder B, Newman R, Jones LK, Debernardi S, Debernardi S, Young BD, Freemont P, Verrijzer CP, Saha Vet al., 2000, Biochemical analyses of the AF10 protein: The extended LAP/PHD-finger mediates oligomerisation (vol 299, pg 369, 2000), JOURNAL OF MOLECULAR BIOLOGY, Vol: 302, Pages: 523-523, ISSN: 0022-2836

Journal article

Bárdos JI, Saurin AJ, Tissot C, Duprez E, Freemont PSet al., 2000, HPC3 is a new human polycomb orthologue that interacts and associates with RING1 and Bmi1 and Has transcriptional repression properties, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 275, Pages: 28785-28792, ISSN: 0021-9258

Journal article

Huyton T, Bates PA, Zhang XD, Sternberg MJE, Freemont PSet al., 2000, The BRCA1 C-terminal domain: structure and function, MUTATION RESEARCH-DNA REPAIR, Vol: 460, Pages: 319-332, ISSN: 0921-8777

Journal article

Linder B, Newman R, Jones LK, Debernardi S, Young BD, Freemont P, Verrijzer CP, Saha Vet al., 2000, Biochemical analyses of the AF10 protein: The extended LAP/PHD-finger mediates oligomerisation, JOURNAL OF MOLECULAR BIOLOGY, Vol: 299, Pages: 369-378, ISSN: 0022-2836

Journal article

Rothwell DG, Hang B, Gorman MA, Freemont PS, Singer B, Hickson IDet al., 2000, Substitution of Asp-210 in HAP1 (APE/Ref-1) eliminates endonuclease activity but stabilises substrate binding, NUCLEIC ACIDS RESEARCH, Vol: 28, Pages: 2207-2213, ISSN: 0305-1048

Journal article

Zhong S, Müller S, Ronchetti S, Freemont PS, Dejean A, Pandolfi PPet al., 2000, Role of SUMO-1-modified PML in nuclear body formation, BLOOD, Vol: 95, Pages: 2748-2753, ISSN: 0006-4971

Journal article

Freemont PS, 2000, RING for destruction?, Curr Biol, Vol: 10, Pages: R84-R87, ISSN: 0960-9822

Ubiquitination targets proteins for degradation and is a potent regulator of cellular protein function. Recent results implicate the RING finger domain in specific ubiquitination events; it is possible that all RING proteins act as E3 ubiquitin protein ligases, with implications for a variety of biological areas.

Journal article

Freemont PS, 2000, Ubiquitination: RING for destruction?, CURRENT BIOLOGY, Vol: 10, Pages: R84-R87, ISSN: 0960-9822

Journal article

Lariviere L, Rueger W, Freemont P, Morera Set al., 2000, β-Glucosyltranferase: Substrate Binding and metal site., Publisher: INT UNION CRYSTALLOGRAPHY, Pages: S242-S242, ISSN: 2053-2733

Conference paper

Zhong S, Müller S, Ronchetti S, Freemont P, Dejean A, Pandolfi PPet al., 1999, PML is essential for proper formation of the nuclear body., BLOOD, Vol: 94, Pages: 489A-489A, ISSN: 0006-4971

Journal article

Müller JMM, Rabouille C, Newman R, Shorter J, Freemont P, Schiavo G, Warren G, Shima DTet al., 1999, An NSF function distinct from ATPase-dependent SNARE disassembly is essential for Golgi membrane fusion, NATURE CELL BIOLOGY, Vol: 1, Pages: 335-340, ISSN: 1465-7392

Journal article

Moréra S, Imberty A, Aschke-Sonnenborn U, Rüger W, Freemont PSet al., 1999, T4 phage β-glucosyltransferase:: Substrate binding and proposed catalytic mechanism, JOURNAL OF MOLECULAR BIOLOGY, Vol: 292, Pages: 717-730, ISSN: 0022-2836

Journal article

Imberty A, Monier C, Bettler E, Morera S, Freemont P, Sippl M, Flöckner H, Rüger W, Breton Cet al., 1999, Fold recognition study of α3-galactosyltransferase and molecular modeling of the nucleotide sugar-binding domain, GLYCOBIOLOGY, Vol: 9, Pages: 713-722, ISSN: 0959-6658

Journal article

Karow JK, Newman RH, Freemont PS, Hickson IDet al., 1999, Oligomeric ring structure of the Bloom's syndrome helicase, CURRENT BIOLOGY, Vol: 9, Pages: 597-600, ISSN: 0960-9822

Journal article

Lu PJ, Sundquist K, Baeckstrom D, Poulsom R, Hanby A, Meier-Ewert S, Jones T, Mitchell M, Pitha-Rowe P, Freemont P, Taylor-Papadimitriou Jet al., 1999, A novel gene (<i>PLU-1</i>) containing highly conserved putative DNA chromatin binding motifs is specifically up-regulated in breast cancer, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 274, Pages: 15633-15645, ISSN: 0021-9258

Journal article

Soulez M, Saurin AJ, Freemont PS, Knight JCet al., 1999, SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex, ONCOGENE, Vol: 18, Pages: 2739-2746, ISSN: 0950-9232

Journal article

Assier E, Bouzinba-Segard H, Stolzenberg MC, Stephens R, Bardos J, Freemont P, Charron D, Trowsdale J, Rich Tet al., 1999, Isolation, sequencing and expression of RED, a novel human gene encoding an acidic-basic dipeptide repeat, GENE, Vol: 230, Pages: 145-154, ISSN: 0378-1119

Journal article

Allford S, Grimwade D, Langabeer S, Duprez E, Saurin A, Chatters S, Walker H, Roberts P, Rogers J, Bain B, Patterson K, McKernan A, Freemont P, Solomon E, Burnett A, Goldstone A, Linch Det al., 1999, Identification of the t(15;17) in AML FAB types other than M3:: evaluation of the role of molecular screening for the <i>PML/RAR</i>α rearrangement in newly diagnosed AML, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 105, Pages: 198-207, ISSN: 0007-1048

Journal article

Allford S, Grimwade D, Langabeer S, Duprez E, Saurin A, Chatters S, Walker H, Roberts P, Rogers J, Bain B, Patterson K, McKernan A, Freemont P, Solomon E, Burnett A, Goldstone A, Linch Det al., 1999, Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARalpha rearrangement in newly diagnosed AML. The Medical Research Council (MRC) Adult Leukaemia Working Party., Br J Haematol, Vol: 105, Pages: 198-207, ISSN: 0007-1048

Acute promyelocytic leukaemia (APL) is characterized by the t(15;17) leading to the formation of PML-RARalpha and RARalpha-PML fusion genes; this rearrangement has been considered both diagnostic for, and restricted to, this subtype of acute myeloid leukaemia (AML FAB M3). We describe two cases of AML with the t(15;17) associated with a PML/RARalpha rearrangement which lacked typical APL morphology, classified as FAB M1 and M2 respectively. In both cases morphological review revealed small populations of cells which exhibited some features associated with APL. In the case classified as M1, PML immunofluorescence studies revealed the classic microparticulate nuclear staining pattern as observed in typical cases of APL with the t(15;17). Similarly, blasts from this case were found to be sensitive to ATRA in vitro as determined by NBT reduction test and by normalization of the PML nuclear body staining pattern. To determine the frequency of PML/RARalpha rearrangements in FAB subtypes other than M3, 530 patients from the MRC AML trials were screened using nested RT-PCR. Only one individual, initially classified as M5 with a normal karyotype, was found to have a PML/RARalpha rearrangement. The diagnosis was revised to M3 variant on subsequent morphological review. In conclusion, this study demonstrates that, in rare cases, the t(15;17) is not restricted to patients with M3 morphology as defined by current FAB criteria. Therefore, although we consider cytogenetic analysis of newly diagnosed cases of AML to be mandatory, our data suggests that routine molecular screening for PML/RARalpha rearrangements is not justified and should be reserved for those cases displaying features which may be suspicious of APL even if such cells comprise only a minority of the total population.

Journal article

Duprez E, Saurin AJ, Desterro JM, Lallemand-Breitenbach V, Howe K, Boddy MN, Solomon E, de Thé H, Hay RT, Freemont PSet al., 1999, SUMO-1 modification of the acute promyelocytic leukaemia protein PML:: implications for nuclear localisation, JOURNAL OF CELL SCIENCE, Vol: 112, Pages: 381-393, ISSN: 0021-9533

Journal article

Lally JM, Dokurno P, Taylor-Papadimitriou J, Freemont PSet al., 1999, CRYSTAL STRUCTURE OF THE SM3 ANTIBODY AGAINST POLYMORPHIC EPITHELIAL MUCIN, Publisher: INT UNION CRYSTALLOGRAPHY, Pages: 351-351, ISSN: 2053-2733

Conference paper

Zhang X, Morera S, Bates PA, Whitehead PC, Coffer AI, Hainbucher K, Nash RA, Sternberg MJE, Lindahl T, Freemont PSet al., 1999, STRUCTURE OF AN XRCC1 BRCT DOMAIN: A NEW PROTEIN PROTEIN INTERACTION MODULE., Publisher: INT UNION CRYSTALLOGRAPHY, Pages: 292-292, ISSN: 2053-2733

Conference paper

Dokurno P, Bates PA, Band HA, Stewart LMD, Lally JM, Burchell JM, Taylor-Papadimitriou J, Snary D, Sternberg MJE, Freemont PSet al., 1998, Crystal structure at 1.95 Å resolution of the breast tumour-specific antibody SM3 complexed with its peptide epitope reveals novel hypervariable loop recognition, JOURNAL OF MOLECULAR BIOLOGY, Vol: 284, Pages: 713-728, ISSN: 0022-2836

Journal article

Bates PA, Dokurno P, Freemont PS, Sternberg MJEet al., 1998, Conformational analysis of the first observed non-proline <i>cis</i>-peptide bond occurring within the complementarity determining region (CDR) of an antibody, JOURNAL OF MOLECULAR BIOLOGY, Vol: 284, Pages: 549-555, ISSN: 0022-2836

Journal article

Zhang XD, Moréra S, Bates PA, Whitehead PC, Coffer AI, Hainbucher K, Nash RA, Sternberg MJE, Lindahl T, Freemont PSet al., 1998, Structure of an XRCC1 BRCT domain:: a new protein-protein interaction module, EMBO JOURNAL, Vol: 17, Pages: 6404-6411, ISSN: 0261-4189

Journal article

Hodges M, Tissot C, Freemont PS, 1998, Protein regulation: Tag wrestling with relatives of ubiquitin, CURRENT BIOLOGY, Vol: 8, Pages: R749-R752, ISSN: 0960-9822

Journal article

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