Different roles of the human Orc6 protein in the replication initiation process

In eukaryotes, binding of the six-subunit origin recognition complex (ORC) to DNA provides an interactive platform for the sequential assembly of pre-replicative complexes. This process licenses replication origins competent for the subsequent initiation step. Here, we analyze the contribution of human Orc6, the smallest subunit of ORC, to DNA binding and pre-replicative complex formation. We show that Orc6 not only interacts with Orc1–Orc5 but also with the initiation factor Cdc6. Biochemical and imaging experiments reveal that this interaction is required for licensing DNA replication competent. Furthermore, we demonstrate that Orc6 contributes to the interaction of ORC with the chaperone protein HMGA1a (high mobility group protein A1a). Binding of human ORC to replication origins is not specified at the level of DNA sequence and the functional organization of origins is poorly understood. We have identified HMGA1a as one factor that might direct ORC to AT-rich heterochromatic regions. The systematic analysis of the interaction between ORC and HMGA1a revealed that Orc6 interacts with the acidic C-terminus of HMGA1a and also with its AT-hooks. Both domains support autonomous replication if targeted to DNA templates. As such, Orc6 functions at different stages of the replication initiation process. Orc6 can interact with ORC chaperone proteins such as HMGA1a to facilitate chromatin binding of ORC and is also an essential factor for pre-RC formation.     

“Without Ub I am nothing”: NEMO as a multifunctional player in ubiquitin-mediated control of NF-κB activation

Ubiquitination has emerged over the years as the most sophisticated way to modify proteins to affect their fate and function. In particular, it has been reported to be instrumental in regulating several steps of the NF-κB signalling pathway which controls inflammation, immunity, adhesion and cell survival. Integrating ubiquitination into NF-κB activation requires the regulatory subunit of IKK, NEMO, which not only displays affinity for polyubiquitin chains, but is also posttranslationally modified by a complex set of reactions involving ubiquitin. Here, we examine how studies of the NEMO/ubiquitin relationship have provided novel insights into the IKK activation process and have uncovered molecular mechanisms that should represent in the future attractive targets for specifically modulating NF-κB function.     

Boltzmann's H-theorem, its discontents, and the birth of statistical mechanics

A comparison is made of the traditional Loschmidt (reversibility) and Zermelo (recurrence) objections to Boltzmann's H-theorem, and its simplified variant in the Ehrenfests’ 1912 wind-tree model. The little-cited 1896 (measure-theoretic) objection of Zermelo (similar to an 1889 argument due to Poincaré) is also analysed. Significant differences between the objections are highlighted, and several old and modern misconceptions concerning both them and the H-theorem are clarified. We give particular emphasis to the radical nature of Poincaré's and Zermelo's attack, and the importance of the shift in Boltzmann's thinking in response to the objections taken together.