Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs

ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress

Maintaining stability of replication forks is important for genomic integrity. However, it is not clear how replisome proteins contribute to fork stability under replication stress. Here, we report that ATAD5, a PCNA unloader, plays multiple functions at stalled forks including promoting its restart. ATAD5 depletion increases genomic instability upon hydroxyurea treatment in cultured cells and mice. ATAD5 recruits RAD51 to stalled forks in an ATR kinase-dependent manner by hydroxyurea-enhanced protein-protein interactions and timely removes PCNA from stalled forks for RAD51 recruitment. Consistent with the role of RAD51 in fork regression, ATAD5 depletion inhibits slowdown of fork progression and native 5-bromo-2??-deoxyuridine signal induced by hydroxyurea. Single-molecule FRET showed that PCNA itself acts as a mechanical barrier to fork regression. Consequently, DNA breaks required for fork restart are reduced by ATAD5 depletion. Collectively, our results suggest an important role of ATAD5 in maintaining genome integrity during replication stress

Polymerase δ replicates both strands after homologous recombination-dependent fork restart

To maintain genetic stability DNA must be replicated only once and replication completed even when individual replication forks are inactivated. Because fork inactivation is common, the passive convergence of an adjacent fork is insufficient to rescue all inactive forks. Thus, eukaryotic cells have evolved homologous recombination-dependent mechanisms to restart persistent inactive forks. Completing DNA synthesis via Homologous Recombination Restarted Replication (HoRReR) ensures cell survival, but at a cost. One such cost is increased mutagenesis caused by HoRReR being more error prone than canonical replication. This increased error rate implies that the HoRReR mechanism is distinct from that of a canonical fork. Here we exploit the fission yeast Schizosaccharomyces pombe to demonstrate that a DNA sequence duplicated by HoRReR during S phase is replicated semi-conservatively, but that both the leading and lagging strands are synthesised by DNA polymerase delta

Impact Evaluation of Productive Use – An Implementation Guideline for Electrification Projects

There is a consensus in the international community that rural electrification and, in particular, the productive use of electricity contributes to poverty alleviation. At the same time, efforts to evaluate the impacts of development projects have increased substantially. This paper provides a hands-on guide for designing evaluation studies regarding the impacts of productive electricity usage. Complementary to the existing literature on evaluation methods, this guide familiarizes project managers with the concrete steps that have to be undertaken to plan and implement an evaluation. The guide comprises three modules based on enterprise surveys and on anecdotal case studies. For each module, the implementation is described on a step-by-step basis including conceptual issues as well as logistics and methodological questions

Evaluating Rural Electrification Projects - Methodological Approaches

In recent years, the international community has expanded efforts in programme evaluation to improve the accountability of development projects. This paper presents approaches to implementing state-of-the-art evaluations in rural electrification projects, taking into account specific challenges that researchers face in such interventions. Furthermore, it suggests a particular approach to assess impacts before an intervention is implemented by surveying the yet non-electrified target region of the project and, in addition, an already electrified region. Besides delivering robust evidence on impacts, results from such ex-ante evaluations provide insights for the project design, thereby reducing the gap between evaluation researchers and practitioners

Need-driven dementia-compromised behavior: An alternative view of disruptive behavior

The disruptive behavior of persons with dementia is a problem of considerable clinical interest and growing scientific concern. This paper offers a view of these behaviors as expressions of unmet needs or goals and provides a comprehensive conceptual framework to guide further research and clinical practice. Empiricalfindings and clinical impressions related to wandering, vocalizations and aggression to support and illustrate the framework are presentedPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66887/2/10.1177_153331759601100603.pd

The Long-Term Consequences of the Global 1918 Influenza Pandemic: A Systematic Analysis of 117 IPUMS International Census Data Sets

Several country-level studies, including a prominent one for the United States, have identified long-term effects of in-utero exposure to the 1918 influenza pandemic (also known as the Spanish Flu) on economic outcomes in adulthood. In-utero conditions are theoretically linked to adult health and socioeconomic status through the fetal origins or Barker hypothesis. Historical exposure to the Spanish Flu provides a natural experiment to test this hypothesis. Although the Spanish Flu was a global phenomenon, with around 500 million people infected worldwide, there exists no comprehensive global study on its long-term economic effects. We attempt to close this gap by systematically analyzing 117 Census data sets provided by IPUMS International. We do not find consistent global long-term effects of influenza exposure on education, employment and disability outcomes. A series of robustness checks does not alter this conclusion. Our findings indicate that the existing evidence on long-term economic effects of the Spanish Flu is likely a consequence of publication bias

Impacts of Rural Electrification in Rwanda

Rural electrification is believed to contribute to the achievement of the MDG. In this paper, we investigate electrification impacts on different indicators. We use household data that we collected in Rwanda in villages with and without electricity access. We account for self-selection and regional differences by using households from the electrified villages to estimate the probability to connect for all households - including those in the non-electrified villages. Based on these probabilities we identify counterfactual households and find robust evidence for positive effects on lighting usage. Effects on income and children's home studying become insignificant if regional differences are accounted for