MDC1: The art of keeping things in focus

The chromatin structure is important for recognition and repair of DNA damage. Many DNA damage response proteins accumulate in large chromatin domains flanking sites of DNA double-strand breaks. The assembly of these structures—usually termed DNA damage foci—is primarily regulated by MDC1, a large nuclear mediator/adaptor protein that is composed of several distinct structural and functional domains. Here, we are summarizing the latest discoveries about the mechanisms by which MDC1 mediates DNA damage foci formation, and we are reviewing the considerable efforts taken to understand the functional implication of these structure

Chromatin maintenance and dynamics in senescence: a spotlight on SAHF formation and the epigenome of senescent cells

Senescence is a stable proliferation arrest characterized by profound changes in cellular morphology and metabolism as well as by extensive chromatin reorganization in the nucleus. One particular hallmark of chromatin changes during senescence is the formation of punctate DNA foci in DAPI-stained senescent cells that have been called senescence-associated heterochromatin foci (SAHF). While many advances have been made concerning our understanding of the effectors of senescence, how chromatin is reorganized and maintained in senescent cells has remained largely elusive. Because chromatin structure is inherently dynamic, senescent cells face the challenge of developing chromatin maintenance mechanisms in the absence of DNA replication in order to maintain the senescent phenotype. Here, we summarize and review recent findings shedding light on SAHF composition and formation via spatial repositioning of chromatin, with a specific focus on the role of lamin B1 for this process. In addition, we discuss the physiological implication of SAHF formation, the role of histone variants, and histone chaperones during senescence and also elaborate on the more general changes observed in the epigenome of the senescent cells

Spectrum of topics for world congresses and other activities of the International Society for Physical and Rehabilitation Medicine (ISPRM) : a first proposal

Background: One of the objectives of the International Society for Physical and Rehabilitation Medicine is to improve the continuity of World Congresses. This requires the development of an abstract topic list for use in congress announcements and abstract submissions. Methods: An abstract topic list was developed on the basis of the definitions of human functioning and rehabilitation research, which define 5 main areas of research (biosciences in rehabilitation, biomedical rehabilitation sciences and engineering, clinical Physical and Rehabilitation Medicine (PRM) sciences, integrative rehabilitation sciences, and human functioning sciences). For the abstract topic list, these research areas were grouped according to the proposals of congress streams. In a second step, the first version of the list was systematically compared with the topics of the 2003 ISPRM World Congress. Results: The resulting comprehensive abstract topic list contains 5 chapters according to the definition of human functioning and rehabilitation research. Due to the high significance of clinical research, clinical PRM sciences were placed at the top of the list, comprising all relevant health conditions treated in PRM services. For congress announcements a short topic list was derived. Discussion: The ISPRM topic list is sustainable and covers a full range of topics. It may be useful for congresses and elsewhere in structuring research in PRM

4′-Acylated thymidine 5′-triphosphates: a tool to increase selectivity towards HIV-1 reverse transcriptase

4′-Acylated thymidines represent a new class of DNA chain terminators, since they have been shown to act as post-incorporation chain-terminating nucleotides despite the presence of a free 3′-hydroxyl group. Here, we describe the action of the 4′-acetyl- (MeTTP) and 4′-propanoylthymidine 5′-triphosphate (EtTTP) on HIV-1 reverse transcriptase in RNA- and DNA-dependent DNA synthesis and on DNA synthesis catalyzed by the cellular DNA polymerases α, β, δ and ε. MeTTP exhibits a high selectivity towards HIV-1 reverse transcriptase. By the use of the bulkier propanoyl group as the 4′-substituent of the nucleoside 5′-triphosphate, selectivity towards HIV-1 reverse transcriptase could be increased without affecting substrate efficiency. Thus, 4′-modifications may serve as a tool to increase selectivity towards HIV-1 reverse transcriptas

Constitutive phosphorylation of MDC1 physically links the MRE11–RAD50–NBS1 complex to damaged chromatin

The MRE11–RAD50–Nijmegen breakage syndrome 1 (NBS1 [MRN]) complex accumulates at sites of DNA double-strand breaks (DSBs) in microscopically discernible nuclear foci. Focus formation by the MRN complex is dependent on MDC1, a large nuclear protein that directly interacts with phosphorylated H2AX. In this study, we identified a region in MDC1 that is essential for the focal accumulation of the MRN complex at sites of DNA damage. This region contains multiple conserved acidic sequence motifs that are constitutively phosphorylated in vivo. We show that these motifs are efficiently phosphorylated by caseine kinase 2 (CK2) in vitro and directly interact with the N-terminal forkhead-associated domain of NBS1 in a phosphorylation-dependent manner. Mutation of these conserved motifs in MDC1 or depletion of CK2 by small interfering RNA disrupts the interaction between MDC1 and NBS1 and abrogates accumulation of the MRN complex at sites of DNA DSBs in vivo. Thus, our data reveal the mechanism by which MDC1 physically couples the MRN complex to damaged chromatin

Social Innovation (or Why We Need the Civil Society)

Activities enacted by economic and governmental actors at various levels will not be sufficient to achieve the necessary turnaround of our consumption patterns and economic systems. What is needed instead are orchestrated, multilevel, and possibly cross-sectoral approaches that offer new solutions to the grand challenges we currently face. There is growing recognition among scholars that civil society plays an important role in addressing so-called "wicked" social, economic, and environmental problems. In this chapter, we discuss the concept of social innovation, how it can be put into practice, and how it can be scaled

Challenges of Managing Common Resources

Common goods are those natural or man-made resources that serve all members of a particular community and its institutions. Unlike private goods such as cars or mobile phones, all members have free access to commons, i.e., the goods cannot simply be fenced off. As a result, such goods tend to be overused, leading to a loss of welfare-the tragedy of the commons. In this chapter, we discuss the concept of the tragedy of the commons, why it is relevant to global and local environmental problems, and how the social dilemma might be resolved

The Future of Sustainable Business: The Circular Economy

To meet environmental targets, it will be central that we use existing materials more efficiently. Accordingly, the future of sustainable business will be closely linked to our ability to build a circular economy. Companies today usually work with linear business models that assume that goods are disposed of by consumers after use and thus become waste. In contrast, the idea of a circular economy is to maximize the benefits of everything that already exists. In this Chapter, we introduce the concept of circular economy and explain why it is relevant for future ecological and economic development