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Linear interaction between transcription and replication shapes DNA break dynamics

ABSTRACT: Linear interaction between transcription and replication shapes DNA break dynamics

PROVIDER: PRJNA1071650 | ENA |

REPOSITORIES: ENA

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Linear interaction between transcription and replication shapes DNA break dynamics

Project description:Recurrent DNA break clusters (RDCs) are replication and transcription collision hotspots. Through high-resolution replication sequencing and a capture-ligation assay in mouse neural progenitor cells experiencing replication stress, we unraveled the replication fork architecture dictating RDC location and orientation. Most RDC occurs at the replication forks traversing timing transition regions (TTRs), where sparse replication origins connect unidirectional forks. Leftward-moving forks generate telomere-connected DNA double-strand breaks (DSB) while rightward-moving forks lead to centromere-connected DSBs. Strand-specific mapping for DNA-bounded RNA revealed transient DNA:RNA hybrids present at a higher density in RDC than in other actively transcribed long genes. In addition, mapping nascent RNA and RNA polymerase activity revealed that head-to-head interactions between replication and transcription machinery slow down DNA replication, resulting in 60% DSB contribution to the head-on as compared to 60% for co-directional . Our findings revealed TTR as a novel fragile class and highlighted how the linear interaction between transcription and replication impacts genome stability.

2024-03-18 | GSE254765 | GEO

Transcription and DNA Replication Shapes DNA Break Dynamics in Long Neuronal Genes

Project description:Transcription and replication conflict (TRC) are one of the main driving forces for genome instability. Yet, TRC rarely been discussed without the context of DNA:RNA entanglement, rending the role of transcription in other TRC unclear . In neural stem and progenitor cells, genes encode protein regulating neuron adhesion are hotspots for recurrent DNA break clusters (RDC). While RDC-containing genes are all actively transcribed, most RDC lack DNA:RNA entanglement. We demonstrated that, through controlled gain and loss of function genetic approaches, transcription activity is essential while not sufficient to induce RDC formation. In combination of a deep neural network and single-nucleotide resolution DNA break mapping approaches, we found RDC break densities mirror the replication fork dynamics. We demonstrated that, for the first time that, head-on TRC results in higher DNA break density than its co-direction counterparts. In summary, our results revealed that transcription has a higher-level regulatory role that has to be coordinated with DNA replication.

2024-03-18 | GSE233842 | GEO

DNA polymerase Δ synthesizes both strands during break-induced replication

Project description:We applied our ribonucleotide mapping technique HydEn-seq to study DNA polymerase usage during break-induced replication (BIR) in the budding yeast Saccharomyces cerevisiae.

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Germline DNA replication timing shapes mammalian genome composition

Project description:Germline DNA replication timing shapes mammalian genome composition

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DNA polymerase Δ synthesizes both strands during break-induced replication

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Genome architecture shapes evolutionary adaptation to DNA replication stress

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Transcription shapes DNA replication initiation to preserve genome integrity

Project description:Transcription shapes DNA replication initiation to preserve genome integrity

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Replication fork progression during re-replication requires the DNA damage checkpoint and double-strand break repair

Project description:Replication fork progression during re-replication requires the DNA damage checkpoint and double-strand break repair

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TRF1 averts chromatin remodelling, recombination and replication dependent-Break Induced Replication at mouse telomeres

Project description:Telomeric repeat sequences are prone to induce replication stress and one of the core telomere binding proteins, TRF1, is thought to counteract these problems. The molecular mechanisms coming into play upon TRF1 loss were not clearly defined though. This study combines an inducible TRF1 loss with telomere-targeted proteomics to analyze the incurring changes. The results show that loss of TRF1 causes important alterations in telomere associated proteins and the new profile resembles in a number of ways that of cells in which telomeres are maintained by telomerase-independent mechanisms, named ALT. The presence of DNA repair proteins (MRN complex, the SMC5/6 complex), some increases in telomere colocalization with PML bodies, sister chromatid exchanges and clear signs of increased TERRA transcription and mitotic break-induced replication are part of these phenotypes. The data also show that these early ALT phenotypes can be differentiated from drug induced replication stress, and part of this ALT response is conserved in human cells. These studies therefore point to a critical role for TRF1 in preventing the emergence of ALT and hence immortalization of cells. Given that the details for how ALT actually is initiated remained unclear, these findings are an important step forward and will spur new research into that question.

2020-01-22 | PXD017022 | Pride

Nuclear organization and replication timing are coupled through RIF1-PP1 interaction

Project description:Three-dimensional genome organisation and replication timing are known to be correlated, however, it remains unknown whether nuclear architecture overall plays an instructive role in the replication-timing program and, if so, how. Here we demonstrate that RIF1 is a molecular hub that co-regulates both processes. Both nuclear organisation and replication timing depend upon the interaction between RIF1 and PP1. However, whereas nuclear architecture requires the full complement of RIF1 and its interaction with PP1, replication timing is not sensitive to RIF1 dosage. RIF1’s role in replication timing also extends beyond its interaction with PP1. Availing of this separation-of-function approach, we have therefore identified in RIF1 dual function the molecular bases of the co-dependency of the replication-timing program and nuclear architecture.

2021-03-09 | GSE148244 | GEO

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