The impact of transcription-mediated replication stress on genome instability and human disease

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.

Topoisomerase I prevents transcription-replication conflicts at transcription termination sites

“…This replication stress (RS) represents an important cause of genomic instability, and strong evidence in recent years indicates that oncogene-induced RS is a major driver of carcinogenesis and tumor progression. 1 The transcription and replication machineries share the same DNA template, which renders head-on (HO) or codirectional (CD) collisions inevitable. HO collisions are considered as more deleterious to the genomic stability.…”

“…3 R-loops have been proposed to play both positive and negative roles in gene expression and other chromosome functions. 1,3 Many factors have been identified to prevent the formation of R-loops or remove them. These include RNA splicing factors, DNA topoisomerases, RNase H and specialized RNA:DNA helicases.…”

“…These include RNA splicing factors, DNA topoisomerases, RNase H and specialized RNA:DNA helicases. 1,4 The analysis of the genome-wide distribution of R-loops with DNA:RNA hybrid immunoprecipitation and next-generation sequencing (DRIP-seq) revealed that R-loops are abundant structures, covering up to 5% of mammalian genomes. 5 Importantly, R-loops also form preferentially at regions of HO collision between replication and transcription.…”

“…4,7 Recent evidence indicates that deregulated oncogenic pathways increase TRCs in precancerous lesions. 1 Interestingly, these oncogene-induced origins are located within gene bodies and generate forks that are not protected from collisions with RNA polymerases. Moreover, deregulated transcriptional programs may also increase RS in cancer cells.…”

Kronos scRT: a uniform framework for single-cell replication timing analysis

“…The cell-type specific program that regulates the progression of DNA replication during the synthesis phase (S phase) is referred to as replication timing (RT) program 10,11 . It has been reported that RT is altered throughout disease development, such as in cancers and neurological disorders [12][13][14] . In addition, RT has been shown, by others and us, to play an important role in shaping the mutational landscape and impacting genome stability in both normal and cancer cells [15][16][17][18][19] .…”