Molecular basis for the inhibition of HMGA1 proteins by distamycin A

The molecular mechanism for the displacement of HMGA1 proteins from DNA is integral to disrupting their cellular function, which is linked to many metastatic cancers. Chemical shift and NOESY NMR experiments provide structural evidence for the displacement of an AT hook peptide (DNA binding motif of HMGA1 proteins) by both monomeric and dimeric distamycin. However, the displaced AT hook alters distamycin binding by weakening the distamycin:DNA complex, while slowing monomeric distamycin dissociation when AT hook is in excess. The central role of the AT hook was evaluated by monitoring full-length HMGA1a protein binding using fluorescence anisotropy. HMGA1a was effectively displaced by distamycin, but the cooperative binding exhibited by distamycin was eliminated by displaced HMGA1a. Additionally, these studies indicate that HMGA1a is displaced from the DNA by 1 equiv of distamycin, suggesting the ability to develop therapeutics that take advantage of the positively cooperative nature of HMGA1a binding.     

Molecular biology of distal muscular dystrophies--sarcomeric proteins on top

During the last 10 years several muscular dystrophies within the group of distal myopathies have been clarified as to the molecular genetic cause of the disease. Currently, the next steps are carried out to identify the molecular pathogenesis downstream of the gene defects. Some early ideas on what is going on in the muscle cells based on the defect proteins are emerging. However, in no single distal muscular dystrophy these efforts have yet reached the point where direct trials for therapy would have been launched, and in many distal dystrophies the causative gene is still lacking. When comparing the gene defects in the distal dystrophies with the more common proximal muscular dystrophies such as dystrophinopathies or limb-girdle muscular dystrophies, there is a striking difference: the genes for distal dystrophies encode sarcomere proteins whereas the genes for proximal dystrophies more often encode sarcolemmal proteins.     

Molecular biology: silencing unlimited

Heterochromatin domains are essential for normal chromosome functions. The Eri1 ribonuclease is a negative regulator of the RNA interference machinery; recent studies have shown that, in fission yeast lacking Eri1, heterochromatin formation is more promiscuous.     

Ciliate biology: dynamin goes nuclear

Dynamin and dynamin-related proteins (DRPs) mediate an array of membrane fission processes. A Tetrahymena DRP has adopted a new role, assisting in nuclear differentiation, a finding that further highlights these proteins - and this ciliate - as biological innovators.     

蛋白质相互作用调控蛋白质核转运及其功能

蛋白质的核转运是真核生物细胞内发生的重要过程之一,是一大群蛋白质发挥其功能的前提,与细胞正常功能的维持密切相关。蛋白质的核运输通常采用核受体介导的方式进行。此过程非常复杂,需要多种蛋白质的参与,涉及到大量的蛋白质相互作用。本文将综合近年来本领域取得的进展,就蛋白质相互作用参与蛋白质核转运来调节蛋白质的亚细胞定位,进一步在多方面影响细胞以及生物体生理功能的变化进行阐述。     

Molecular radiation biology: Future aspects

Summary Future aspects of molecular radiation biology may be envisaged by looking for unsolved problems and ways to analyse them. Considering the endpoints of cellular radiation effects as cell inactivation, chromosome aberrations, mutation and transformation, the type of DNA damage in the irradiated cell and the mechanisms of DNA repair as excision repair, recombination repair and mutagenic repair are essential topics. At present, great efforts are made to identify, to clone and to sequence genes involved in the control of repair of DNA damage and to study their regulation. There are close relationships between DNA repair genes isolated from various organisms, which promises fast progress for the molecular analysis of repair processes in mammalian cells. More knowledge is necessary regarding the function of the gene products, i.e. enzymes and proteins involved in DNA repair. Effort should be made to analyse the enzymatic reactions, leading to an altered nucleotide sequence, encountered as a point mutation. Mislead mismatch repair and modulation of DNA polymerase might be possible mechanisms.Paper given at the workshop Molecular Radiation Biology. German Section of the DNA Repair Network, München-Neuherberg, 21.–23.3.90