Sites of chromosomal instability in the context of nuclear architecture and function.
Chromosomal fragile sites are described as areas within the tightly packed mitotic chromatin that appear as breaks or gaps mostly tracing back to a loosened structure and not a real nicked break within the DNA molecule. Most facts about fragile sites result from studies in mitotic cells, mainly during metaphase and mainly in lymphocytes. Here, we synthesize facts about the genomic regions that are prone to form gaps and breaks on metaphase chromosomes in the context of interphase. We conclude that nuclear architecture shapes the activity profile of the cell, i.e. replication timing and transcriptional activity, thereby influencing genomic integrity during interphase with the potential to cause fragility in mitosis. We further propose fragile sites as examples of regions specifically positioned in the interphase nucleus with putative anchoring points at the nuclear lamina to enable a tightly regulated replication-transcription profile and diverse signalling functions in the cell. Consequently, fragility starts before the actual display as chromosomal breakage in metaphase to balance the initial contradiction of cellular overgrowth or malfunctioning and maintaining diversity in molecular evolution.
['Pentzold|Constanze|C|http://orcid.org/0000-0003-3711-8945', 'Kokal|Miriam|M|', 'Pentzold|Stefan|S|', 'Weise|Anja|A|']
D000818:Animals D002467:Cell Nucleus D043171:Chromosomal Instability D043283:Chromosome Fragile Sites D004247:DNA D004261:DNA Replication D015894:Genome, Human D006801:Humans D007399:Interphase D008938:Mitosis
Cancer Cell cycle Chromatin organization Chromosome condensation Chromosome territory Replication-transcription conflicts