Genome-wide high-resolution mapping of mitotic DNA synthesis sites and common fragile sites by direct sequencing

Ji, Fang; Liao, Hongwei; Pan, Sheng; Ouyang, Liujian; Jia, Fang; Fu, Zaiyang; Zhang, Fengjiao; Geng, Xinwei; Wang, Xinming; Li, Tingting; Liu, Shuangying; Syeda, Madiha Zahra; Chen, Hạixia; Wen, Li; Chen, Zhihua; Shen, Huahao; Ying, Songmin

doi:10.1038/s41422-020-0357-y

Cited by 48 publications

(44 citation statements)

References 86 publications

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“…There is clearly a need for the development of a good biomarker for DNA replication stress in the clinic, particularly considering that several drugs that target DNA replication stress, including ATR and Chk1 inhibitors, are currently being evaluated in clinical trials. [66][67][68] Thus, the precise mapping of MiDAS regions, reported here and in an accompanying paper, 69 will accelerate the development of reliable clinical biomarkers.…”

Section: Relevance To Cancermentioning

confidence: 77%

High-resolution mapping of mitotic DNA synthesis regions and common fragile sites in the human genome through direct sequencing

et al. 2020

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DNA replication stress, a feature of human cancers, often leads to instability at specific genomic loci, such as the common fragile sites (CFSs). Cells experiencing DNA replication stress may also exhibit mitotic DNA synthesis (MiDAS). To understand the physiological function of MiDAS and its relationship to CFSs, we mapped, at high resolution, the genomic sites of MiDAS in cells treated with the DNA polymerase inhibitor aphidicolin. Sites of MiDAS were evident as well-defined peaks that were largely conserved between cell lines and encompassed all known CFSs. The MiDAS peaks mapped within large, transcribed, origin-poor genomic regions. In cells that had been treated with aphidicolin, these regions remained unreplicated even in late S phase; MiDAS then served to complete their replication after the cells entered mitosis. Interestingly, leading and lagging strand synthesis were uncoupled in MiDAS, consistent with MiDAS being a form of break-induced replication, a repair mechanism for collapsed DNA replication forks. Our results provide a better understanding of the mechanisms leading to genomic instability at CFSs and in cancer cells.

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Section: Relevance To Cancermentioning

confidence: 77%

High-resolution mapping of mitotic DNA synthesis regions and common fragile sites in the human genome through direct sequencing

et al. 2020

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“…CFSs are specific DNA loci prone to exhibit chromosome instability manifested as single-chromatid gaps, breaks and constrictions on metaphase chromosomes after experiencing replication stress in the previous S-phase (as for example, exposure to the DNA polymerase inhibitor aphidicolin -APH- [ 29 ]). The current model posits that CFS fragility is mainly determined by three CFS features: (i) late S-phase replication, (ii) paucity of replication origins and (iii) active transcription due to enrichment in large transcription units [ 25 , 27 , 30 , 31 ]. Moreover, continuous transcription of CFS region throughout S phase could also affect origin availability as it could promote premature eviction of pre-RCs from chromatin preventing their utilization as replication origins [ 30 , 31 ].…”

Section: Under-replication Events Are Frequentmentioning

confidence: 99%

“…MiDAS buffers the detrimental consequences of replication stress suffered in the previous S phase ( Figure 2 , [ 28 , 56 ]). MiDAS is not involved in the repair of DNA DSBs or other forms of DNA damage in mitotic cells but mainly deals with DFS-induced UR-DNA at CFSs [ 27 , 28 , 30 ]. Crucially, not only the replication stress caused by exogenous factors such as APH treatment has been shown to induce MiDAS, but also genetic deficiencies that either slow down replication rate [ 65 ] or disturb origin licensing/firing [ 23 ].…”

Section: Mitotic Dna Repairmentioning

confidence: 99%

Under-Replicated DNA: The Byproduct of Large Genomes?

Bertolin

Hoffmann

Gottifredi

2020

Cancers

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In this review, we provide an overview of how proliferating eukaryotic cells overcome one of the main threats to genome stability: incomplete genomic DNA replication during S phase. We discuss why it is currently accepted that double fork stalling (DFS) events are unavoidable events in higher eukaryotes with large genomes and which responses have evolved to cope with its main consequence: the presence of under-replicated DNA (UR-DNA) outside S phase. Particular emphasis is placed on the processes that constrain the detrimental effects of UR-DNA. We discuss how mitotic DNA synthesis (MiDAS), mitotic end joining events and 53BP1 nuclear bodies (53BP1-NBs) deal with such specific S phase DNA replication remnants during the subsequent phases of the cell cycle.

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“…EdUseq enabled the study of mitotic DNA synthesis (MiDAS), occurring due to replication stress. Two recent reports showed that all CFSs, known to be late replicating and commonly deleted in cancer, colocalize with the mapped MiDAS [113,114]. These studies emphasize how replication stress that carries into mitosis can pose a severe threat to genome integrity, which can lead to tumor progression, thus, providing an understanding of how CFSs are implicated in cancer.…”

Section: New Insights On Misrepair Of Physiological Dsbs In Cancer Cellsmentioning

confidence: 80%

“…These studies emphasize how replication stress that carries into mitosis can pose a severe threat to genome integrity, which can lead to tumor progression, thus, providing an understanding of how CFSs are implicated in cancer. Identification of these sites can serve as a potential biomarker in the clinic [113,114].…”

Section: New Insights On Misrepair Of Physiological Dsbs In Cancer Cellsmentioning

confidence: 99%

Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States

Oster

Aqeilan

2020

Cells

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DNA double strand breaks (DSBs) are known to be the most toxic and threatening of the various types of breaks that may occur to the DNA. However, growing evidence continuously sheds light on the regulatory roles of programmed DSBs. Emerging studies demonstrate the roles of DSBs in processes such as T and B cell development, meiosis, transcription and replication. A significant recent progress in the last few years has contributed to our advanced knowledge regarding the functions of DSBs is the development of many next generation sequencing (NGS) methods, which have considerably advanced our capabilities. Other studies have focused on the implications of programmed DSBs on chromosomal aberrations and tumorigenesis. This review aims to summarize what is known about DNA damage in its physiological context. In addition, we will examine the advancements of the past several years, which have made an impact on the study of genome landscape and its organization.

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Genome-wide high-resolution mapping of mitotic DNA synthesis sites and common fragile sites by direct sequencing

Cited by 48 publications

References 86 publications

High-resolution mapping of mitotic DNA synthesis regions and common fragile sites in the human genome through direct sequencing

High-resolution mapping of mitotic DNA synthesis regions and common fragile sites in the human genome through direct sequencing

Under-Replicated DNA: The Byproduct of Large Genomes?

Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States

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