Regulation of Chk1

Chk1 is a serine/threonine protein kinase that is the effector of the G2 DNA damage checkpoint. Chk1 homologs have a highly conserved N-terminal kinase domain, and a less conserved C-terminal regulatory domain of ~200 residues. In response to a variety of genomic lesions, a number of proteins collaborate to activate Chk1, which in turn ensures that the mitotic cyclin-dependent kinase Cdc2 remains in an inactive state until DNA repair is completed. Chk1 activation requires the phosphorylation of residues in the C-terminal domain, and this is catalyzed by the ATR protein kinase. How phosphorylation of the C-terminal regulatory domain activates the N-terminal kinase domain has not been elucidated, though some studies have suggested that this phosphorylation relieves an inhibitory intramolecular interaction between the N- and C-termini. However, recent studies in the fission yeast Schizosaccharomyces pombe have revealed that there is more to Chk1 regulation than this auto-inhibition model, and we review these findings and their implication to the biology of this genome integrity determinant

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

Checkpoint kinase1 (CHK1) is an important biomarker in breast cancer having a role in chemotherapy response

Background:Checkpoint kinase1 (CHK1), which is a key component of DNA-damage-activated checkpoint signalling response, may have a role in breast cancer (BC) pathogenesis and influence response to chemotherapy. This study investigated the clinicopathological significance of phosphorylated CHK1 (pCHK1) protein in BC.Method:pCHK1 protein expression was assessed using immunohistochemistry in a large, well-characterized annotated series of early-stage primary operable invasive BC prepared as tissue microarray (n=1200).Result:pCHK1 showed nuclear and/or cytoplasmic expression. Tumours with nuclear expression showed positive associations with favourable prognostic features such as lower grade, lower mitotic activity, expression of hormone receptor and lack of expression of KI67 and PI3K (

Cell Division Regulation of Chk1

Abstract Chk1 is a serine/threonine protein kinase that is the effector of the G2 DNA damage checkpoint. Chk1 homologs have a highly conserved N-terminal kinase domain, and a less conserved Cterminal regulatory domain of ~200 residues. In response to a variety of genomic lesions, a number of proteins collaborate to activate Chk1, which in turn ensures that the mitotic cyclin-dependent kinase Cdc2 remains in an inactive state until DNA repair is completed. Chk1 activation requires the phosphorylation of residues in the C-terminal domain, and this is catalyzed by the ATR protein kinase. How phosphorylation of the C-terminal regulatory domain activates the N-terminal kinase domain has not been elucidated, though some studies have suggested that this phosphorylation relieves an inhibitory intramolecular interaction between the N-and C-termini. However, recent studies in the fission yeast Schizosaccharomyces pombe have revealed that there is more to Chk1 regulation than this auto-inhibition model, and we review these findings and their implication to the biology of this genome integrity determinant. Review A little history: control of entry into mitosis and the identification of chk1 The cell cycle is an orderly progression driven by the activities of the cyclin-dependent kinases (CDK) that control the transitions from G1 in S-phase, and from G2 into mitosis. The G2/M transition is particularly ancient in origin and is controlled by a universal mechanism common to virtually all eukaryotes To ensure cells do not enter mitosis prematurely, checkpoints overlay the core cell cycle machinery to ultimatel

SMC complexes and topoisomerase II work together so that sister chromatids can work apart

The pairing of sister chromatids in interphase facilitates error-free homologous recombination (HR). Sister chromatids are held together by cohesin, one of three Structural Maintenance of Chromosomes (SMC) complexes. In mitosis, chromosome condensation is controlled by another SMC complex, condensin, and the type II topoisomerase (Top2). In prophase, cohesin is stripped from chromosome arms, but remains at centromeres until anaphase, whereupon it is removed via proteolytic cleavage. The third SMC complex, Smc5/6, is generally described as a regulator of HR-mediated DNA repair. However, cohesin and condensin are also required for DNA repair, and HR genes are not essential for cell viability, but the SMC complexes are. Smc5/6 null mutants die in mitosis, and in fission yeast, Smc5/6 hypomorphs show lethal mitoses following genotoxic stress, or when combined with a Top2 mutant, top2-191. We found these mitotic defects are due to retention of cohesin on chromosome arms. We also show that Top2 functions in the cohesin cycle, and accumulating data suggests this is not related to its decatenation activity. Thus the SMC complexes and Top2 functionally interact, and any DNA repair function ascribed to Smc5/6 is likely a reflection of a more fundamental role in the regulation of chromosome structure

Beneficios del ejercicio físico en pacientes con enfermedad renal crónica en hemodiálisis

Introducción: La enfermedad renal crónica (ERC) en etapa terminal requiere de tratamiento de sustitución renal como lo es la hemodiálisis. Los pacientes que se someten a este tipo de tratamiento se caracterizan por tener una alta prevalencia de enfermedades cardiovasculares asociadas o exacerbadas por la inactividad física y alteraciones del metabolismo mineral óseo que llevan a presentar también problemas psicológicos y bajos niveles de calidad de vida. Objetivo: Identificar los beneficios del ejercicio en pacientes con ERC que se someten a hemodiálisis. Metodología: Se realizó una revisión bibliográfica en las bases de datos Pubmed, Scielo, Google académico y Pedro. Resultados: Se seleccionaron 25 artículos, donde la información obtenida se organizó de acuerdo a las variables evaluadas en los estudios. Se encontró que el ejercicio en pacientes en HD tiene efectos beneficiosos a nivel cardiovascular, en el metabolismo óseo, en la eliminación de solutos, en la función y capacidad física, a nivel psicológico y en la calidad de vida. Conclusiones: El ejercicio físico tiene una gran cantidad de beneficios para los pacientes en tratamiento dialítico por lo que incluir programas de ejercicios intradialíticos puede ser una forma económica de ayuda a minimizar problemas asociados a la enfermedad renal crónica, no solo en el área fisiológica del paciente, sino también en el área psicológica y social

Beneficios del ejercicio físico en pacientes con enfermedad renal crónica en hemodiálisis

Resumen Introducción: La enfermedad renal crónica (ERC) en etapa terminal requiere de tratamiento de sustitución renal como lo es la hemodiálisis. Los pacientes que se someten a este tipo de tratamiento se caracterizan por tener una alta prevalencia de enfermedades cardiovasculares asociadas o exacerbadas por la inactividad física y alteraciones del metabolismo mineral óseo que llevan a presentar también problemas psicológicos y bajos niveles de calidad de vida. Objetivo: Identificar los beneficios del ejercicio en pacientes con ERC que se someten a hemodiálisis. Metodología: Se realizó una revisión bibliográfica en las bases de datos Pubmed, Scielo, Google académico y Pedro. Resultados: Se seleccionaron 25 artículos, donde la información obtenida se organizó de acuerdo a las variables evaluadas en los estudios. Se encontró que el ejercicio en pacientes en HD tiene efectos beneficiosos a nivel cardiovascular, en el metabolismo óseo, en la eliminación de solutos, en la función y capacidad física, a nivel psicológico y en la calidad de vida. Conclusiones: El ejercicio físico tiene una gran cantidad de beneficios para los pacientes en tratamiento dialítico por lo que incluir programas de ejercicios intradialíticos puede ser una forma económica de ayudar a minimizar problemas asociados a la enfermedad renal crónica, no solo en el área fisiológica del paciente, sino también en el área psicológica y social