SUMOylation promotes de novo targeting of HP1α to pericentric heterochromatin.

International audienceHP1 enrichment at pericentric heterochromatin is considered important for centromere function. Although HP1 binding to H3K9me3 can explain its accumulation at pericentric heterochromatin, how it is initially targeted there remains unclear. Here, in mouse cells, we reveal the presence of long nuclear noncoding transcripts corresponding to major satellite repeats at the periphery of pericentric heterochromatin. Furthermore, we find that major transcripts in the forward orientation specifically associate with SUMO-modified HP1 proteins. We identified this modification as SUMO-1 and mapped it in the hinge domain of HP1α. Notably, the hinge domain and its SUMOylation proved critical to promote the initial targeting of HP1α to pericentric domains using de novo localization assays, whereas they are dispensable for maintenance of HP1 domains. We propose that SUMO-HP1, through a specific association with major forward transcript, is guided at the pericentric heterochromatin domain to seed further HP1 localization

MAREJADAS RURALES Y LUCHAS POR LA VIDA, VOL. III: VAIVENES DEL ESTADO Y LA SOCIEDAD RURAL.

Volumen 3. Vaivenes del Estado y la Sociedad Rural, coordinado por: Francisco Herrera Tapia, Gladys Karina Sánchez Juárez, e Ignacio López Moreno, el texto está constituído por 12 capítulos, los autores abordan problemas derivados de la aplicación de las políticas públicas y reformas legislativas relacionadas con el campo, y con las instituciones de gobierno, la gobernabilidad, los acuerdos comunitarios y también los conflictos, son estudios de caso que evidencian estos procesos y las formas en que se complejizan o se resuelven en el medio rural.ASOCIACIÓN MEXICANA DE ESTUDIOS RURALES A.C., INSTITUTO DE CIENCIAS AGROPECUARIAS Y RURALES (ICAR), UNIVERSIDAD DE GUADALAJARA, EL COLEGIO DE MICHOACÁN A.C., UNIVERSIDAD MICHOACANA DE SAN NICOLAS HIDALGO, CUCOSTA SUR GRANA, ECOSUR, FACULTAD DE ESTUDIOS SUPERIORES ACATLÁN-UNA

Phosphorylation and DNA Binding of HJURP Determine Its Centromeric Recruitment and Function in CenH3CENP-A Loading

Centromeres, epigenetically defined by the presence of the histone H3 variant CenH3, are essential for ensuring proper chromosome segregation. In mammals, centromeric CenH3CENP-A deposition requires its dedicated chaperone HJURP and occurs during telophase/early G1. We find that the cell-cycle-dependent recruitment of HJURP to centromeres depends on its timely phosphorylation controlled via cyclin-dependent kinases. A nonphosphorylatable HJURP mutant localizes prematurely to centromeres in S and G2 phase. This unregulated targeting causes a premature loading of CenH3CENP-A at centromeres, and cell-cycle delays ensue. Once recruited to centromeres, HJURP functions to promote CenH3CENP-A deposition by a mechanism involving a unique DNA-binding domain. With our findings, we propose a model wherein (1) the phosphorylation state of HJURP controls its centromeric recruitment in a cell-cycle-dependent manner, and (2) HJURP binding to DNA is a mechanistic determinant in CenH3CENP-A loading

La Constitución Política de los Estados Unidos Mexicanos 1917-2017 a 100 años

resultado de la primera revolución social del siglo XX fue la Constitución Política de los Estados Unidos Mexicanos, documento que plasmó las aspiraciones de toda una nación, marcando el rumbo de nuestro país hacia la democracia. Gracias a la Carta Magna hoy tenemos garantizados amplios derechos y podemos ejercer plenamente nuestras libertades. Celebro que la Universidad Autónoma del Estado de México conmemore los cien años de nuestra Constitución con la publicación de este libro, elaborado por un grupo multidisciplinario de investigadores, pertenecientes a diversas instituciones educativas del país, que analizan los diferentes artículos de la Constitución de 1917, desde los ámbitos histórico, filosófico, jurídico, educativo y social. Para el Gobierno del Estado de México, un libro conmemorativo de nuestra Carta Magna es invitación a reflexionar sobre las características de nuestras instituciones, así como la conveniencia de mantener o reformar sus artículos para continuar respondiendo a las necesidades de la ciudadanía. En cada propuesta de este libro, desde sus respectivos campos de estudio, los autores analizan los retos de la sociedad actual; además en su lectura e interpretación demuestran que los 136 artículos no son letra muerta, siguen vigentes

Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses In Vivo

International audienceB-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to rechallenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8 þ T cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance antitumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell-directed checkpoint modulators

Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.

The development of novel agents has transformed the treatment paradigm for multiple myeloma (MM), with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in MM patients. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory MM, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in MM is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes