Sites of chromosomal instability in the context of nuclear architecture and function
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Cellular and Molecular Life Sciences
REVIEW
Sites of chromosomal instability in the context of nuclear architecture and function Constanze Pentzold1 · Miriam Kokal1 · Stefan Pentzold2 · Anja Weise1 Received: 15 May 2020 / Revised: 2 October 2020 / Accepted: 31 October 2020 © The Author(s) 2020
Abstract 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. Keywords Cancer · Cell cycle · Chromatin organization · Chromosome condensation · Chromosome territory · Replicationtranscription conflicts
Chromosomal fragile sites within the replicative landscape of the nucleus The dilemma of cellular division Developing organisms rely on cell division (mitotic cells) to distribute their genetic material equally and ideally errorless to subsequent daughter cells. During differentiation most cells do not continue to divide (postmitotic cells) and transition into senescence while the whole organism is ageing. For a long time, this course into cellular expiration by telomere shortening was thought to counteract cellular division progress into malignant overgrowth [1]. However, the constraint of mutational accumulation as a positive effect faces the secretion of tissue disrupting substances by senescent cells * Constanze Pentzold [email protected]‑jena.de 1
Institute of Human Genetics, University Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany
Research Center Lobeda, Jena University Hospital, 07747 Jena, Germany
2
as negative effect [2, 3]. Concomitantly, cellular division continues even in mature organisms to some extent specifically to function for tissue maintenance and regeneration. Every cell is exposed to up to thousands of single lesions from exogenous and endogenous sources to mostly challenge the integrity of the genetic material within one generation when affecting somatic cells [4, 5]. However, when germ cells are affected, mutations can
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