Le Forum, Vol. 40 No. 4

https://digitalcommons.library.umaine.edu/francoamericain_forum/1089/thumbnail.jp

Le Forum, Vol. 41 No. 2

https://digitalcommons.library.umaine.edu/francoamericain_forum/1091/thumbnail.jp

Le Forum, Vol. 41 No. 3

https://digitalcommons.library.umaine.edu/francoamericain_forum/1092/thumbnail.jp

Le Forum, Vol. 44 #2

https://digitalcommons.library.umaine.edu/francoamericain_forum/1104/thumbnail.jp

Polar oceans and sea ice in a changing climate

Polar oceans and sea ice cover 15% of the Earth’s ocean surface, and the environment is changing rapidly at both poles. Improving knowledge on the interactions between the atmospheric and oceanic realms in the polar regions, a Surface Ocean–Lower Atmosphere Study (SOLAS) project key focus, is essential to understanding the Earth system in the context of climate change. However, our ability to monitor the pace and magnitude of changes in the polar regions and evaluate their impacts for the rest of the globe is limited by both remoteness and sea-ice coverage. Sea ice not only supports biological activity and mediates gas and aerosol exchange but can also hinder some in-situ and remote sensing observations. While satellite remote sensing provides the baseline climate record for sea-ice properties and extent, these techniques cannot provide key variables within and below sea ice. Recent robotics, modeling, and in-situ measurement advances have opened new possibilities for understanding the ocean–sea ice–atmosphere system, but critical knowledge gaps remain. Seasonal and long-term observations are clearly lacking across all variables and phases. Observational and modeling efforts across the sea-ice, ocean, and atmospheric domains must be better linked to achieve a system-level understanding of polar ocean and sea-ice environments. As polar oceans are warming and sea ice is becoming thinner and more ephemeral than before, dramatic changes over a suite of physicochemical and biogeochemical processes are expected, if not already underway.These changes in sea-ice and ocean conditions will affect atmospheric processes by modifying the production of aerosols, aerosol precursors, reactive halogens and oxidants, and the exchange of greenhouse gases. Quantifying which processes will be enhanced or reduced by climate change calls for tailored monitoring programs for high-latitude ocean environments. Open questions in this coupled system will be best resolved by leveraging ongoing international and multidisciplinary programs, such as efforts led by SOLAS, to link research across the ocean–sea ice–atmosphere interface

RAP80 Targets BRCA1 to Specific Ubiquitin Structures at DNA Damage Sites

Mutations affecting the BRCT domains of the breast cancer–associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-γH2AX–dependent lysine6 - and lysine63-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs

Le Forum, Vol. 43 No. 2

https://digitalcommons.library.umaine.edu/francoamericain_forum/1100/thumbnail.jp

Alu elements mediate MYB gene tandem duplication in human T-ALL

Recent studies have demonstrated that the MYB oncogene is frequently duplicated in human T cell acute lymphoblastic leukemia (T-ALL). We find that the human MYB locus is flanked by 257-bp Alu repeats and that the duplication is mediated somatically by homologous recombination between the flanking Alu elements on sister chromatids. Nested long-range PCR analysis indicated a low frequency of homologous recombination leading to MYB tandem duplication in the peripheral blood mononuclear cells of ∼50% of healthy individuals, none of whom had a MYB duplication in the germline. We conclude that Alu-mediated MYB tandem duplication occurs at low frequency during normal thymocyte development and is clonally selected during the molecular pathogenesis of human T-ALL

Heterogeneity and Clonal Evolution of Acquired PARP Inhibitor Resistance in TP53- and BRCA1-Deficient Cells

Homologous recombination (HR)-deficient cancers are sensitive to poly- ADP ribose polymerase inhibitors (PARPi), which have shown clinical efficacy in the treatment of high-grade serous cancers (HGSC). However, the majority of patients will relapse, and acquired PARPi resistance is emerging as a pressing clinical problem. Here we generated seven single-cell clones with acquired PARPi resistance derived from a PARPi-sensitive TP53(-/-) and BRCA1(-/-) epithelial cell line generated using CRISPR/Cas9. These clones showed diverse resistance mechanisms, and some clones presented with multiple mechanisms of resistance at the same time. Genomic analysis of the clones revealed unique transcriptional and mutational profiles and increased genomic instability in comparison with a PARPi-sensitive cell line. Clonal evolutionary analyses suggested that acquired PARPi resistance arose via clonal selection from an intrinsically unstable and heterogenous cell population in the sensitive cell line, which contained preexisting drug-tolerant cells. Similarly, clonal and spatial heterogeneity in tumor biopsies from a clinical patient with BRCA1-mutant HGSC with acquired PARPi resistance was observed. In an imaging-based drug screening, the clones showed heterogenous responses to targeted therapeutic agents, indicating that not all PARPi-resistant clones can be targeted with just one therapy. Furthermore, PARPi-resistant clones showed mechanism-dependent vulnerabilities to the selected agents, demonstrating that a deeper understanding on the mechanisms of resistance could lead to improved targeting and biomarkers for HGSC with acquired PARPi resistance. Significance: This study shows that BRCA1-deficient cells can give rise to multiple genomically and functionally heterogenous PARPi-resistant clones, which are associated with various vulnerabilities that can be targeted in a mechanism-specific manner.Peer reviewe

Alu elements mediate MYB gene tandem duplication in human T-ALL

Recent studies have demonstrated that the MYB oncogene is frequently duplicated in human T cell acute lymphoblastic leukemia (T-ALL). We find that the human MYB locus is flanked by 257-bp Alu repeats and that the duplication is mediated somatically by homologous recombination between the flanking Alu elements on sister chromatids. Nested long-range PCR analysis indicated a low frequency of homologous recombination leading to MYB tandem duplication in the peripheral blood mononuclear cells of ∼50% of healthy individuals, none of whom had a MYB duplication in the germline. We conclude that Alu-mediated MYB tandem duplication occurs at low frequency during normal thymocyte development and is clonally selected during the molecular pathogenesis of human T-ALL