Recognition of Double Strand Breaks by a Mutator Protein (MU2) in Drosophila melanogaster

Telomere capture, a rare event that stabilizes chromosome breaks, is associated with certain genetic abnormalities in humans. Studies pertaining to the generation, maintenance, and biological effects of telomere formation are limited in metazoans. A mutation, mu2a, in Drosophila melanogaster decreases the rate of repair of double strand DNA breaks in oocytes, thus leading to chromosomes that have lost a natural telomere and gained a new telomere. Amino acid sequence, domain architecture, and protein interactions suggest that MU2 is an ortholog of human MDC1. The MU2 protein is a component of meiotic recombination foci and localizes to repair foci in S2 cells after irradiation in a manner similar to that of phosphorylated histone variant H2Av. Domain searches indicated that the protein contains an N-terminal FHA domain and a C-terminal tandem BRCT domain. Peptide pull-down studies showed that the BRCT domain interacts with phosphorylated H2Av, while the FHA domain interacts with the complex of MRE11, RAD50, and NBS. A frameshift mutation that eliminates the MU2 BRCT domain decreases the number and size of meiotic phospho-H2Av foci. MU2 is also required for the intra-S checkpoint in eye-antennal imaginal discs. MU2 participates at an early stage in the recognition of DNA damage at a step that is prerequisite for both DNA repair and cell cycle checkpoint control. We propose a model suggesting that neotelomeres may arise when radiation-induced chromosome breaks fail to be repaired, fail to arrest progression through meiosis, and are deposited in the zygote, where cell cycle control is absent and rapid rounds of replication and telomere formation ensue

Collaborative Contagion: A Case Study in Curriculum Development, Distribution, and Adoption

The collaborative contagion model is the culmination of a three‐year project designed first to develop a curriculum in business ethics and entrepreneurship (BE&E), then to increase the adoption of that curriculum by leveraging professional educators’ established networks. The development of a new curriculum, the collaborative portion of the program, was accomplished through a series of four‐day, in‐person disruptive innovation workshops (DIWs), after which educators continued their working relationships in a specially developed online community. To distribute this curriculum, we developed the contagion portion of the model, through which we encouraged and incentivized not only adoption of the curriculum on the part of the participants themselves, but also on the part of people in their broader networks. After our first year of workshops, 18 K‐12 and 21 higher education participants helped formulate 10 modules and 60 grade‐specific K‐12 lesson plans. We have established pilot programs at 13 separate institutions, and built partnerships with seven organizations. These early results indicate that the collaborative contagion model is a viable, and potentially strong method by which curricular materials can be developed, and then disseminated to a broad audience

Chapter Telomere Maintenance in Organisms without Telomerase

Biochemistr

Telomere Maintenance in Organisms without Telomerase

Biochemistr

MU2 and HP1a Regulate the Recognition of Double Strand Breaks in Drosophila melanogaster

Chromatin structure regulates the dynamics of the recognition and repair of DNA double strand breaks; open chromatin enhances the recruitment of DNA damage response factors, while compact chromatin is refractory to the assembly of radiation-induced repair foci. MU2, an orthologue of human MDC1, a scaffold for ionizing radiation-induced repair foci, is a widely distributed chromosomal protein in Drosophila melanogaster that moves to DNA repair foci after irradiation. Here we show using yeast 2 hybrid screens and co-immunoprecipitation that MU2 binds the chromoshadow domain of the heterochromatin protein HP1 in untreated cells. We asked what role HP1 plays in the formation of repair foci and cell cycle control in response to DNA damage. After irradiation repair foci form in heterochromatin but are shunted to the edge of heterochromatic regions an HP1-dependent manner, suggesting compartmentalized repair. Hydroxyurea-induced repair foci that form at collapsed replication forks, however, remain in the heterochromatic compartment. HP1a depletion in irradiated imaginal disc cells increases apoptosis and disrupts G2/M arrest. Further, cells irradiated in mitosis produced more and brighter repair foci than to cells irradiated during interphase. Thus, the interplay between MU2 and HP1a is dynamic and may be different in euchromatin and heterochromatin during DNA break recognition and repair

Selective antagonism of cJun for cancer therapy

The activator protein-1 (AP-1) family of transcription factors modulate a diverse range of cellular signalling pathways into outputs which can be oncogenic or anti-oncogenic. The transcription of relevant genes is controlled by the cellular context, and in particular by the dimeric composition of AP-1. Here, we describe the evidence linking cJun in particular to a range of cancers. This includes correlative studies of protein levels in patient tumour samples and mechanistic understanding of the role of cJun in cancer cell models. This develops an understanding of cJun as a focal point of cancer-altered signalling which has the potential for therapeutic antagonism. Significant work has produced a range of small molecules and peptides which have been summarised here and categorised according to the binding surface they target within the cJun-DNA complex. We highlight the importance of selectively targeting a single AP-1 family member to antagonise known oncogenic function and avoid antagonism of anti-oncogenic function

Some Spinor-Curvature Identities

We describe a class of spinor-curvature identities which exist for Riemannian or Riemann-Cartan geometries. Each identity relates an expression quadratic in the covariant derivative of a spinor field with an expression linear in the curvature plus an exact differential. Certain special cases in 3 and 4 dimensions which have been or could be used in applications to General Relativity are noted.Comment: 5 pages Plain TeX, NCU-GR-93-SSC