Insights into common fragile site instability: DNA replication challenges at DNA repeat sequences

Michal Irony Tur Sinai, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

Common fragile sites (CFS) are specific genomic regions prone to chromosomal instability under conditions of DNA replication stress. CFSs manifest as breaks, gaps, and constrictions on metaphase chromosomes under mild replication stress. These replication-sensitive CFS regions are preferentially unstable during cancer development, as reflected by their association with copy number variants (CNVs) frequently arise in most tumor types. Over the years, it became clear that a combination of different characteristics underlies the enhanced sensitivity of CFSs to replication stress. As of today, there is a strong evidence that the core fragility regions along CFSs overlap with actively transcribed large genes with delayed replication timing upon replication stress. Recently, the mechanistic basis for CFS instability was further extended to regions which span topologically associated domain (TAD) boundaries, generating a fragility signature composed of replication, transcription and genome organization. The presence of difficult-to-replicate AT-rich repeats was one of the early features suggested to characterize a subgroup of CFSs. These long stretches of AT-dinucleotide have the potential to fold into stable secondary structures which may impede replication fork progression, leaving the region under-replicated. Here, we focus on the molecular mechanisms underlying repeat instability at CFSs and on the proteins involved in the resolution of secondary structure impediments arising along repetitive sequence elements which are essential for the maintenance of genome stability.

Original languageAmerican English
Pages (from-to)277-287
Number of pages11
JournalEmerging topics in life sciences
Volume7
Issue number3
DOIs
StatePublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 Portland Press Ltd. All rights reserved.

Fingerprint

Dive into the research topics of 'Insights into common fragile site instability: DNA replication challenges at DNA repeat sequences'. Together they form a unique fingerprint.

Cite this