Nuclear microenvironments in biological control and cancer

Abstract

Nucleic acids and regulatory proteins are compartmentalized in microenvironments within the nucleus. This subnuclear organization may support convergence and the integration of physiological signals for the combinatorial control of gene expression, DNA replication and repair. Nuclear organization is modified in many cancers. There are cancer-related changes in the composition, organization and assembly of regulatory complexes at intranuclear sites. Mechanistic insights into the temporal and spatial organization of machinery for gene expression within the nucleus, which is compromised in tumours, provide a novel platform for diagnosis and therapy.

The role of nuclear organization in cancer

“…They either activate or repress transcription, depending on their posttranslational modifications and the availability of cofactors [107]. RUNX proteins localize to discrete domains in the nucleus, emphasizing the compartmentalization of regulatory proteins to specific nuclear microenvironments [3].…”

“…Furthermore, specific mutations of RUNX1 are found in haematological malignancies and RUNX3 in gastric cancer. These result in defective nuclear localization, with the proteins being retained in the cytoplasm or showing aberrant subnuclear targeting, and a dysregulation of hundreds of target genes [3].…”

“…It is now recognized as playing a fundamental role in regulating the activities of the genome and also as being abnormal in cancer [2][3][4]. Changes in nuclear shape, nucleoplasmic texture and number of nucleoli are traditionally used to distinguish cancer cells from their normal counterparts at the cytological level [4,5].…”

Genomic Imprinting and Epigenetic Control of Development

“…In many cases the formation of these loops is directly linked to gene expression patterns, suggesting a broad, structural mechanism for transcriptional regulation. It is therefore not surprising that mutation of CTCF and cohesin, as well as misregulation of nuclear architecture, have been observed in cancers and number of human diseases (Zaidi et al 2007). For example, mutation of a structural component of the nuclear membrane, LMNA, is associated with numerous diseases including a form of progeria ( premature aging).…”

High content image cytometry in the context of subnuclear organization

“…Diverse biological processes, such as DNA repair (19), senescence (20), apoptosis (21), and transformation (22) are associated with specific nuclear protein location patterns. Conversely, mislocalization of nuclear proteins, due to mutations, is associated with specific diseases, such as laminopathies, progeroid syndromes, and cancer (23,24). Therefore, nuclear organization may prove a valuable indicator for a variety of pathologies.…”