The impact of transcription-mediated replication stress on genome instability and human disease
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REVIEW ARTICLE
The impact of transcription‑mediated replication stress on genome instability and human disease Stefano Gnan1,2 · Yaqun Liu1,2 · Manuela Spagnuolo1,2 · Chun‑Long Chen1,2 Received: 6 May 2020 / Revised: 31 July 2020 / Accepted: 21 August 2020 / Published online: 30 August 2020 © The Author(s) 2020
Abstract DNA replication is a vital process in all living organisms. At each cell division, > 30,000 replication origins are activated in a coordinated manner to ensure the duplication of > 6 billion base pairs of the human genome. During differentiation and development, this program must adapt to changes in chromatin organization and gene transcription: its deregulation can challenge genome stability, which is a leading cause of many diseases including cancers and neurological disorders. Over the past decade, great progress has been made to better understand the mechanisms of DNA replication regulation and how its deregulation challenges genome integrity and leads to human disease. Growing evidence shows that gene transcription has an essential role in shaping the landscape of genome replication, while it is also a major source of endogenous replication stress inducing genome instability. In this review, we discuss the current knowledge on the various mechanisms by which gene transcription can impact on DNA replication, leading to genome instability and human disease. Keyword DNA replication program · Replication stress · Genome instability · Cell cycle · Transcription–replication conflicts · R-loops · Common fragile sites · Cancers · Neurological disorders Abbreviations ARS Autonomously replicating sequence BIR Break-induced replication BRCA1/2 Breast-related cancer antigen 1/2 CD Co‑directional CDC45/6 Cell division control protein 45/6 CDK Cyclin-dependent kinase CDT1 CDC10-dependent transcript 1 CFS Common fragile site DDK Dbf4-Dependent Kinase; DDR DNA damage response DSB DNA double-strand break ER Estrogen receptor ERFS Early-replicating fragile site ESC Embryonic stem cell FA Fanconi anemia Yaqun Liu and Manuela Spagnuolo have contributed equally to this work. * Chun‑Long Chen [email protected] 1
Curie Institute, PSL Research University, CNRS, UMR 3244, 75005 Paris, France
Sorbonne University, 75005 Paris, France
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FISH Fluorescence in situ hybridization FXS Fragile X syndrome G4 G quadruplex HO Head-on HR Homologous recombination MCM Mini-chromosome maintenance MiDAS Mitotic DNA synthesis NHEJ Non-homologous end joining NSPC Neural stem/progenitor cell ODP Origin decision point OGRE Origin G-rich repeated elements OK-seq Okazaki fragment sequencing ORC Origin recognition complex PCNA Proliferating cell nuclear antigen pre-IC Pre-initiation complex pre-RC Pre‑replication complex RDC Recurrent DSB cluster RFC Replication factor C Rif1 Rap1-interacting factor 1 RPA Replication protein A RT Replication timing SDR Significant delayed region SNS Small nascent strand TAD Topologically associated domain TDP Time decision point
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