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The RecQ-like helicase BLM cooperates with topoisomerase IIIα, RMI1, and RMI2 in a heterotetrameric complex (the "Bloom syndrome complex") for dissolution of double Holliday junctions, key intermediates in homologous recombination. Mutations in any component of the Bloom syndrome complex can cause genome instability and a highly cancer-prone disorder called Bloom syndrome. Some heterozygous carriers are also predisposed to breast cancer. To understand how the activities of BLM helicase and topoisomerase IIIα are coupled, we purified the active four-subunit complex. Chemical cross-linking and mass spectrometry revealed a unique architecture that links the helicase and topoisomerase domains. Using biochemical experiments, we demonstrated dimerization mediated by the N terminus of BLM with a 2:2:2:2 stoichiometry within the Bloom syndrome complex. We identified mutations that independently abrogate dimerization or association of BLM with RMI1, and we show that both are dysfunctional for dissolution using in vitro assays and cause genome instability and synthetic lethal interactions with GEN1/MUS81 in cells. Truncated BLM can also inhibit the activity of full-length BLM in mixed dimers, suggesting a putative mechanism of dominant-negative action in carriers of BLM truncation alleles. Our results identify critical molecular determinants of Bloom syndrome complex assembly required for double Holliday junction dissolution and maintenance of genome stability. [ABSTRACT FROM AUTHOR]

In response to Larry Silver (EC 231 774) concerning whether attention deficit-hyperactivity disorder is a learning disability via a related disorder, this article proposes an interactional perspective that stresses the educational needs of the child within his/her total environmental context. It also summarizes the current empirical and clinical knowledge concerning these children. (DB)

Site-specific conjugation of ubiquitin onto a range of DNA repair proteins regulates their critical functions in the DNA damage response. Biochemical and structural characterization of these functions are limited by an absence of tools for the purification of DNA repair proteins in purely the ubiquitinated form. To overcome this barrier, we designed a ubiquitin fusion protein that is N-terminally biotinylated and can be conjugated by E3 RING ligases onto various substrates. Biotin affinity purification of modified proteins, followed by cleavage of the affinity tag leads to release of natively-mono-ubiquitinated substrates. As proof-of-principle, we applied this method to several substrates of mono-ubiquitination in the Fanconi anemia (FA)-BRCA pathway of DNA interstrand crosslink repair. These include the FANCI:FANCD2 complex, the PCNA trimer and BRCA1 modified nucleosomes. This method provides a simple approach to study the role of mono-ubiquitination in DNA repair or any other mono-ubiquitination signaling pathways. [ABSTRACT FROM AUTHOR]

Reviews the history and revisions of core curriculums in higher institutions of learning. Each school may be characterized by the priority of values it observes in its curricular structure. To the academic advisor, the values the curriculum represents are the trail markers that define the guide's terrain. (Author/BEF)

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by skin rash (poikiloderma), skeletal dysplasia, small stature, juvenile cataracts, sparse or absent hair, and predisposition to specific malignancies such as osteosarcoma and hematological neoplasms. RTS is caused by germ-line mutations in RECQL4, a RecQ helicase family member. In vitro studies have identified functions for the ATP-dependent helicase of RECQL4. However, its specific role in vivo remains unclear. To determine the physiological requirement and the biological functions of Recql4 helicase activity, we generated mice with an ATP-binding-deficient knock-in mutation (Recql4K525A). Recql4K525A/K525A mice were strikingly normal in terms of embryonic development, body weight, hematopoiesis, B and T cell development, and physiological DNA damage repair. However, mice bearing two distinct truncating mutations Recql4G522Efs and Recql4R347*, that abolished not only the helicase but also the C-terminal domain, developed a profound bone marrow failure and decrease in survival similar to a Recql4 null allele. These results demonstrate that the ATP-dependent helicase activity of Recql4 is not essential for its physiological functions and that other domains might contribute to this phenotype. Future studies need to be performed to elucidate the complex interactions of RECQL4 domains and its contribution to the development of RTS. [ABSTRACT FROM AUTHOR]

X-ray diffraction studies on a series of cationic divalent metal domplexes supported by the tris(1-isopropyl-4-tert-butylimidazolyl)phosphine ligand, {[pim(super Pr(super i),Bu(super t))]M(NO3)}(super +) (M = Co, Cu, Zn, Cd, Hg), demonstrate that the nitrate ligand coordination mode is strongly dependent upon the metal. In view of the steric demands of two ligand systems, the fine-tuning that is necessary to create synthetic analogues that accurately mimic the chemistry of metalloenzymes is accentuated.

Summary Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs. [ABSTRACT FROM AUTHOR]

Mo(PMe3)6 reacts with ArOH (Ar=2,4,6-C6H2Me3, 2,6-C6H3Pri2) to give coordinatively unsaturated aryloxy-hydride derivatives Mo(PMe3)4(OAr)H. The formation of Mo(PMe3)4(OAr)H is in marked contrast to the cyclometalated products of C&z.sbnd;H bond activation that are obtained for the corresponding tungsten system. Deuterium labeling and magnetization transfer studies, however, demonstrate that the coordinatively unsaturated molybdenum complexes Mo(PMe3)4(OAr)H are in fact kinetically capable of intramolecular oxidative addition of a C&z.sbnd;H bond of the ortho substituents to yield cyclometalated derivatives that are thermodynamically unstable with respect to the aryloxy-hydride derivatives. [Copyright &y& Elsevier]

Describes the synthesis of Mo(PMe3)6 and the thermodynamic details of the equilibrium of Mo(PMe3)6 with its cyclometalated derivative Mo(PMe3)4(eta2-CH2PMe2)H and PMe3. Mechanism of synthesis; Equilibration thermodynamics; Use of the trimethylphosphine complexes in the syntheses of terminal sulfido, selenido, and tellurido complexes of molybdenum.

Presents a study to determine eight-coordinate tungsten hydride complexes' molecular structures, using singled-crystal X-ray diffraction. Similarities of the molecular structures, with reference to the trigonal dodecahedron; In-depth look at the chloride ligands; Methodology used to conduct the study; Results of the study.

Determines the structures of bis(pyrazolylethyl) ether derivatives of zinc and colbalt with a view to addressing the applicability of such ligands in modeling the NNO donor environment in thermolysin. What is demonstrated by structural studies; Comparison of nitrate coordination models of ligands in bis(nitrate) complexes.