Abstract
Simple SummaryChromosome instability (CIN) is characterized by an increased accumulation of numerical and structural changes in chromosomes and is a common feature of solid tumors and some hematological malignancies. CIN has been extensively linked to tumorigenesis, cancer progression, and tumor resistance. However, in recent years CIN phenotypes are increasingly being harnessed for therapeutic purposes. In this review, we describe the origins of structural CIN phenotypes and highlight novel pathways for their resolution. We also discuss how CIN can be avoided or enhanced and the implications of these pathways for cell survival and thus, cancer treatments.Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly being considered as a possible therapeutic target, raising the question of which variables may convert CIN into an ally instead of an enemy during cancer treatment. This review discusses the origins of structural chromosome abnormalities and the cellular mechanisms that prevent and resolve them, as well as how different CIN phenotypes relate to each other. We discuss the possible fates of cells containing structural CIN, focusing on how a few cell duplication cycles suffice to induce profound CIN-mediated genome alterations. Because such alterations can promote tumor adaptation to treatment, we discuss currently proposed strategies to either avoid CIN or enhance CIN to a level that is no longer compatible with cell survival.
Highlights
Genomic stability is conserved by the coordinated activity of multiple genome maintenance pathways that ensure faithful DNA replication and equal distribution of duplicated DNA among daughter cells [1]
Because the S to G2 transition is triggered seemingly by the absence of replication and not by the finalization of DNA replication [28], cells enter mitosis with such under-replicated DNA (UR-DNA) regions. If they are still not duplicated by the end of M phase, such UR-DNA regions can lead to non-disjunction, giving rise to Ultra-Fine Bridges (UFBs) [29,30,31]
Structural Chromosome instability (CIN) is a common feature of solid tumors, and the last decades have yielded a great understanding of the molecular mechanisms that give rise
Summary
Genomic stability is conserved by the coordinated activity of multiple genome maintenance pathways that ensure faithful DNA replication and equal distribution of duplicated DNA among daughter cells [1]. These pathways include cell cycle checkpoints, DNA damage detection and its repair, telomere maintenance, and centrosome duplication, to name a few Their defects lead to genomic instability, a state with an increased tendency to acquire genetic alterations. Structural CIN is commonly associated with replication stress (stalled or collapsed replication forks), telomere dysfunction, and errors in the repair of double-strand breaks (DSBs) [9,10]. Despite their apparently distinct origins, it is worth mentioning that both numerical and structural CIN tend to coexist in tumors, and each can be the source of the other [10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
