RESUMEN
The dynamic compartmental organization of the transcriptional machinery in mammalian nuclei places particular constraints on the spatial organization of the genome. The clustering of active RNA polymerase I transcription units from several chromosomes at nucleoli is probably the best-characterized and universally accepted example. RNA polymerase II localization in mammalian nuclei occurs in distinct concentrated foci that are several-fold fewer in number compared to the number of active genes and transcription units. Individual transcribed genes cluster at these shared transcription factories in a nonrandom manner, preferentially associating with heterologous, coregulated genes. We suggest that the three-dimensional (3D) conformation and relative arrangement of chromosomes in the nucleus has a major role in delivering tissue-specific gene-expression programs.
Asunto(s)
Núcleo Celular/genética , Genoma/genética , Transcripción Genética , Animales , Células Eritroides/metabolismo , Genes , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , ARN no Traducido/metabolismoAsunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Drosophila/genética , Impresión Genómica , Proteínas Nucleares/genética , ARN no Traducido/genética , Proteínas Represoras/genética , Elementos Silenciadores Transcripcionales , Animales , Animales Modificados Genéticamente , Sitios de Unión/genética , Factor de Unión a CCCTC , Metilación de ADN , Proteínas de Unión al ADN/metabolismo , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Evolución Molecular , Femenino , Genes de Insecto , Elementos Aisladores , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Ratones , Modelos Genéticos , Proteínas Nucleares/metabolismo , ARN Largo no Codificante , Proteínas Represoras/metabolismo , Eliminación de SecuenciaRESUMEN
Two alleles of the Drosophila melanogaster Rfc4 (DmRfc4) gene, which encodes subunit 4 of the replication factor C (RFC) complex, cause striking defects in mitotic chromosome cohesion and condensation. These mutations produce larval phenotypes consistent with a role in DNA replication but also result in mitotic chromosomal defects appearing either as premature chromosome condensation-like or precocious sister chromatid separation figures. Though the DmRFC4 protein localizes to all replicating nuclei, it is dispersed from chromatin in mitosis. Thus the mitotic defects appear not to be the result of a direct role for RFC4 in chromosome structure. We also show that the mitotic defects in these two DmRfc4 alleles are the result of aberrant checkpoint control in response to DNA replication inhibition or damage to chromosomes. Not all surveillance function is compromised in these mutants, as the kinetochore attachment checkpoint is operative. Intriguingly, metaphase delay is frequently observed with the more severe of the two alleles, indicating that subsequent chromosome segregation may be inhibited. This is the first demonstration that subunit 4 of RFC functions in checkpoint control in any organism, and our findings additionally emphasize the conserved nature of RFC's involvement in checkpoint control in multicellular eukaryotes.