The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks inmammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136

SJG-136, a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer, is a highly efficient interstrand crosslinking agent that reacts with guanine bases in a 5'-GATC-3' sequence in the DNA minor groove. SJG-136 crosslinks form rapidly and persist compared to those produced by conventional crosslinking agents such as nitrogen mustard, melphalan or cisplatin which bind in the DNA major groove. A panel of Chinese hamster ovary (CHO) cells with defined defects in specific DNA repair pathways were exposed to the bi-functional agents SJG-136 and melphalan, and to their mono-functional analogues mmy-SJG and mono-functional melphalan. SJG-136 was >100 times more cytotoxic than melphalan, and the bi-functional agents were much more cytotoxic than their respective mono-functional analogues. Cellular sensitivity of both SJG-136 and melphalan was dependent on the XPF-ERCC1 heterodimer, and homologous recombination repair factors XRCC2 and XRCC3. The relative level of sensitivity of these repair mutant cell lines to SJG-136 was, however, significantly less than with major groove crosslinking agents. In contrast to melphalan, there was no clear correlation between sensitivity to SJG-136 and crosslink unhooking capacity measured using a modified comet assay. Furthermore, repair of SJG-136 crosslinks did not involve the formation of DNA double-strand breaks. SJG-136 cytotoxicity is likely to result from the poor recognition of DNA damage by repair proteins resulting in the slow repair of both mono-adducts and more importantly crosslinks in the minor groove

Narrative Improvisations: Balzac’s “Facino Cane”

In this discussion intended to complement existing studies of Facino Cane, it is argued that Balzac’s short narrative is the product of a persistent reflection on storytelling and on the status of the composition as writing. Balzac is shown to make extensive reference to a range of other texts including Les Mille et Une Nuits and Dante’s Inferno, while his representation of the blind musicians is shown to relate similarly to a prominent literary and graphic tradition that begins with Montesquieu and takes in, for example, L.-S. Mercier, E. de Jouy, and contemporary Parisian guidebooks. There follows an examination of the distinctive play on proper names and of the way the text is generated by a select number of associative chains. It is claimed that the perceptible ambiguities of the composition stem from this self-reflexive and ludic art of improvisation

Poetry, image, and post-Napoleonic politics: Baudelaire’s “Le Squelette laboureur”

Dans les planches d’anatomieQui traînent sur ces quais poudreuxOù maint livre cadavéreuxDort comme une antique momie, Dites, quelle moisson étrange,Forçats arrachés au charnier,Tirez-vous, et de quel fermierAvez-vous à remplir la grange? Dessins auxquels la gravitéEt le savoir d’un vieil artiste,Bien que le sujet en soit triste,Ont communiqué la Beauté, Voulez-vous (d’un destin trop durÉpouvantable et clair emblème!)Montrer que dans la fosse mêmeLe sommeil promis n’est pas sûr; On voit, ce q..

Nerval’s “Antéros”: towards an intertextual reading

The opœning line of Nerval’s sonnet Antéros (Tu me demandes pourquoi j’ai tant de rage au cœur) does not reveal the speaker’s identity. Swayed by the presence elsewhere in Les Chimères of a voice that encourages identification with the poet himself, the reader is likely, at least initially, to entertain the notion that, here too, it is the poet who is speaking (especially given the reader’s lack of a rival for the position of addressee), even if there is obvious interference from the presence..

γH2AX Foci Form Preferentially in Euchromatin after Ionising-Radiation

BACKGROUND: The histone variant histone H2A.X comprises up to 25% of the H2A complement in mammalian cells. It is rapidly phosphorylated following exposure of cells to double-strand break (DSB) inducing agents such as ionising radiation. Within minutes of DSB generation, H2AX molecules are phosphorylated in large chromatin domains flanking DNA double-strand breaks (DSBs); these domains can be observed by immunofluorescence microscopy and are termed gammaH2AX foci. H2AX phosphorylation is believed to have a role mounting an efficient cellular response to DNA damage. Theoretical considerations suggest an essentially random chromosomal distribution of X-ray induced DSBs, and experimental evidence does not consistently indicate otherwise. However, we observed an apparently uneven distribution of gammaH2AX foci following X-irradiation with regions of the nucleus devoid of foci. METHODOLOGY/PRINCIPLE FINDINGS: Using immunofluorescence microscopy, we show that focal phosphorylation of histone H2AX occurs preferentially in euchromatic regions of the genome following X-irradiation. H2AX phosphorylation has also been demonstrated previously to occur at stalled replication forks induced by UV radiation or exposure to agents such as hydroxyurea. In this study, treatment of S-phase cells with hydroxyurea lead to efficient H2AX phosphorylation in both euchromatin and heterochromatin at times when these chromatin compartments were undergoing replication. This suggests a block to H2AX phosphorylation in heterochromatin that is at least partially relieved by ongoing DNA replication. CONCLUSIONS/SIGNIFICANCE: We discuss a number of possible mechanisms that could account for the observed pattern of H2AX phosphorylation. Since gammaH2AX is regarded as forming a platform for the recruitment or retention of other DNA repair and signaling molecules, these findings imply that the processing of DSBs in heterochromatin differs from that in euchromatic regions. The differential responses of heterochromatic and euchromatic compartments of the genome to DSBs will have implications for understanding the processes of DNA repair in relation to nuclear and chromatin organization

Shanidar et ses fleurs? Reflections on the palynology of the Neanderthal ‘Flower Burial’ hypothesis

Pollen clumps associated with the skeleton of the Shanidar 4 Neanderthal were interpreted by the excavator as evidence for a purposeful burial with flowers. This was one of several findings from Shanidar Cave that helped to shape modern perceptions of Neanderthals as sharing empathic characteristics with Middle Palaeolithic Homo sapiens (modern humans). Here the available evidence is reviewed critically from a palynological viewpoint. It seems likely that at least some of the pollen clumps were emplaced by nesting solitary bees, though other mechanisms may also have been involved. Shanidar 4 remains of notable importance, however, in being part of a tight cluster of remarkably complete and deliberately emplaced Neanderthal skeletal remains

The Viscous Nonlinear Dynamics of Twist and Writhe

Exploiting the "natural" frame of space curves, we formulate an intrinsic dynamics of twisted elastic filaments in viscous fluids. A pair of coupled nonlinear equations describing the temporal evolution of the filament's complex curvature and twist density embodies the dynamic interplay of twist and writhe. These are used to illustrate a novel nonlinear phenomenon: ``geometric untwisting" of open filaments, whereby twisting strains relax through a transient writhing instability without performing axial rotation. This may explain certain experimentally observed motions of fibers of the bacterium B. subtilis [N.H. Mendelson, et al., J. Bacteriol. 177, 7060 (1995)].Comment: 9 pages, 4 figure