AT-dinucleotide rich sequences drive fragile site formation

Sinai, Michal Irony-Tur; Salamon, Anita; Stanleigh, Noemie; Goldberg, Tchelet; Weiss, Aryeh; Wang, Yuh‐Hwa; Kerem, Batsheva

doi:10.1093/nar/gkz689

Cited by 30 publications

(24 citation statements)

References 54 publications

(96 reference statements)

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“…Poly dA:dT tracks have been involved in the instability of early-replicating fragile sites (ERFS), another type of instable sequences associated with short, highly transcribed and early-replicating genes 42,43 . In addition, a recent report has shown that a 3.4 kb dA:dT dinucleotide sequence targeted to the 40 kb long early-replicating HGPRT gene triggers instability of this house-keeping gene 44 . Therefore, sequences able to form secondary structures may become instable in some chromosome contexts, notably ERFS, but not in the context of modestly transcribed large late-replicating genes.…”

Section: Discussionmentioning

confidence: 99%

Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide

et al. 2019

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Common fragile sites (CFSs) are chromosome regions prone to breakage upon replication stress known to drive chromosome rearrangements during oncogenesis. Most CFSs nest in large expressed genes, suggesting that transcription could elicit their instability; however, the underlying mechanisms remain elusive. Genome-wide replication timing analyses here show that stress-induced delayed/under-replication is the hallmark of CFSs. Extensive genomewide analyses of nascent transcripts, replication origin positioning and fork directionality reveal that 80% of CFSs nest in large transcribed domains poor in initiation events, replicated by long-travelling forks. Forks that travel long in late S phase explains CFS replication features, whereas formation of sequence-dependent fork barriers or head-on transcriptionreplication conflicts do not. We further show that transcription inhibition during S phase, which suppresses transcription-replication encounters and prevents origin resetting, could not rescue CFS stability. Altogether, our results show that transcription-dependent suppression of initiation events delays replication of large gene bodies, committing them to instability.

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Section: Discussionmentioning

confidence: 99%

Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide

et al. 2019

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“…Yet another possibility is that the DNA sequences present within the CFSs may be inherently difficult to replicate due to their propensity to adopt atypical secondary structures. 16,[32][33][34][35][36] Interestingly, treatment of cells with aphidicolin leads not only to breaks and gaps on mitotic chromosomes, but also to foci of nascent DNA synthesis that decorate these chromosomes. 37 These foci represent sites of so-called mitotic DNA synthesis (MiDAS), and generally colocalize with FANCD2 foci and with ultrafine anaphase bridges, which mark the chromosomal positions of CFSs in cells exposed to aphidicolin.…”

Section: Introductionmentioning

confidence: 99%

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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“…4 d). Though the biological significances of the other 102 peaks are not reported as many SSRs being lacking of understanding in human Y-DNA originally, these peaks may also play some important biological roles potentially, which probably deserve to be further explored [ 6 , 10 , 42 – 45 ]. In addition, those middle and low peaks possibly be also helpful to some biological process.…”

Section: Discussionmentioning

confidence: 99%

A comprehensive microsatellite landscape of human Y-DNA at kilobase resolution

Pan

Zhang

et al. 2021

BMC Genomics

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Background Though interest in human simple sequence repeats (SSRs) is increasing, little is known about the exact distributional features of numerous SSRs in human Y-DNA at chromosomal level. Herein, totally 540 maps were established, which could clearly display SSR landscape in every bin of 1 k base pairs (Kbp) along the sequenced part of human reference Y-DNA (NC_000024.10), by our developed differential method for improving the existing method to reveal SSR distributional characteristics in large genomic sequences. Results The maps show that SSRs accumulate significantly with forming density peaks in at least 2040 bins of 1 Kbp, which involve different coding, noncoding and intergenic regions of the Y-DNA, and 10 especially high density peaks were reported to associate with biological significances, suggesting that the other hundreds of especially high density peaks might also be biologically significant and worth further analyzing. In contrast, the maps also show that SSRs are extremely sparse in at least 207 bins of 1 Kbp, including many noncoding and intergenic regions of the Y-DNA, which is inconsistent with the widely accepted view that SSRs are mostly rich in these regions, and these sparse distributions are possibly due to powerfully regional selection. Additionally, many regions harbor SSR clusters with same or similar motif in the Y-DNA. Conclusions These 540 maps may provide the important information of clearly position-related SSR distributional features along the human reference Y-DNA for better understanding the genome structures of the Y-DNA. This study may contribute to further exploring the biological significance and distribution law of the huge numbers of SSRs in human Y-DNA.

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AT-dinucleotide rich sequences drive fragile site formation

Cited by 30 publications

References 54 publications

Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide

Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide

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

A comprehensive microsatellite landscape of human Y-DNA at kilobase resolution

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