Recent advances in donor-acceptor (DA) cyclopropanes

Two major mechanisms have been causally implicated in the establishment of cellular senescence: the activation of the DNA damage response (DDR) pathway and the formation of senescence-associated heterochromatic foci (SAHF). Here we show that in human fibroblasts resistant to premature p16(INK4a) induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli. Oncogene-induced SAHF formation depends on DNA replication and ATR (ataxia telangiectasia and Rad3-related). Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction. In human cancers, levels of heterochromatin markers are higher than in normal tissues, and are independent of the proliferative index or stage of the tumours. Pharmacological and genetic perturbation of heterochromatin in oncogene-expressing cells increase DDR signalling and lead to apoptosis. In vivo, a histone deacetylase inhibitor (HDACi) causes heterochromatin relaxation, increased DDR, apoptosis and tumour regression. These results indicate that heterochromatin induced by oncogenic stress restrains DDR and suggest that the use of chromatin-modifying drugs in cancer therapies may benefit from the study of chromatin and DDR status of tumours.

Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer

Syntheses and ring opening reactions of vicinally donor-acceptor-substituted cyclopropanes are treated in this review. Special attention is directed to methyl 2-siloxy cyclopropanecarboxylates which display an particularly rich and versatile chemistry leading to synthesis of polyfunctional compounds, certain carbocycles, and heterocyclic systems. Other classes of donor-acceptor-substituted cyclopropanes are also regarded emphasizing new developments. Although preparative aspects are strongly accentuated, interesting mechanistic features, characteristic for this type of three-membered rings, will also be discussed.

Donor-Acceptor-Substituted Cyclopropanes: Versatile Building Blocks in Organic Synthesis

Transition-metal catalyzed decomposition of aliphatic diazo compounds — New results and applications in organic synthesis

The mammalian heart loses its regenerative potential soon after birth. Adult cardiac myocytes (ACMs) permanently exit the cell cycle, and E2F-dependent genes are stably silenced, although the underlying mechanism is unclear. Heterochromatin, which silences genes in many biological contexts, accumulates with cardiac differentiation. H3K9me3, a histone methylation characteristic of heterochromatin, also increases in ACMs and at E2F-dependent promoters. We hypothesize that genes relevant for cardiac proliferation are targeted to heterochromatin by retinoblastoma (Rb) family members interacting with E2F transcription factors and recruiting heterochromatin protein 1 (HP1) proteins. To test this hypothesis, we created cardiac-specific Rb and p130 inducible double knockout (IDKO) mice. IDKO ACMs showed a decrease in total heterochromatin, and cell cycle genes were derepressed, leading to proliferation of ACMs. Although Rb/p130 deficiency had no effect on total H3K9me3 levels, recruitment of HP1-γ to promoters was lost. Depleting HP1-γ up-regulated proliferation-promoting genes in ACMs. Thus, Rb and p130 have overlapping roles in maintaining the postmitotic state of ACMs through their interaction with HP1-γ to direct heterochromatin formation and silencing of proliferation-promoting genes.

https://rupress.org/jcb/article-pdf/194/3/407/1352115/jcb_201012049.pdf

Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes

Synthese von 2-siloxysubstituierten Cyclopropancarbonsäure-methylestern

Ringöffnungsreaktionen von 2‐Siloxycyclopropancarbonsäuremethylestern zu 4‐Oxoalkansäurederivaten

Interaction between HP1α and replication proteins in mammalian cells

A replication fork barrier at the 3'-end of mouse ribosomal RNA genes blocks bidirectional fork progression and limits DNA replication to the same direction as transcription. This barrier is an inherent property of a defined DNA-protein complex including transcription termination factor I, and specific protein-protein interactions occur between this factor and protein(s) of the replication machinery. Here we report that a second DNA-binding protein is essential for barrier activity. We have purified and functionally characterised the protein from HeLa cells. The final preparation contained two polypeptides with molecular masses of 70 and 86 kDa, respectively. Both polypeptides interact with a GC-stretch adjacent to the binding site of transcription termination factor I. The specificity of binding to the barrier DNA was demonstrated in an electrophoretic mobility shift assay. The biochemical properties of this protein resemble that of Ku antigen, a human nuclear DNA-binding heterodimer that is the target of autoimmune-antibodies in several autoimmune diseases. Recombinant Ku protein, purified as heterodimer from co-infected insect cells, is able to partially rescue the barrier activity in Ku-depleted HeLa cell extracts. These data demonstrate that transcription termination factor I and Ku act synergistically to prevent head-on collision between the replication and the transcription machinery.

Ku antigen supports termination of mammalian rDNA replication by transcription termination factor TTF-I.

Die Cyclopropane (I) lassen sich unter milden Bedingungen und in sehr hoher Ausb., wie an einigen Beispielen gezeigt, in Ester des Typs (II) (grostenteils Diastereomerengemische), die als Synthesebausteine von Bedeutung sind, uberfuhren.

Ring opening reactions of methyl 2‐silyloxycyclopropanecarboxylates to 4‐oxoalkanoic acid derivatives

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