Eukaryotic Replication Barriers: How, Why and Where Forks Stall

Dalgaard, Jacob Z.; Godfrey, Emma; MacFarlane, Ramsay J.

doi:10.5772/20383

DNA Replication-Current Advances 2011

DOI: 10.5772/20383

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Eukaryotic Replication Barriers: How, Why and Where Forks Stall

Jacob Z. Dalgaard¹,

Emma Godfrey²,

Ramsay J. MacFarlane³

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Cited by 2 publications

(1 citation statement)

References 156 publications

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“…The replication fork barrier (RFB) site near the 3= end of the pre-rRNA coding region has been identified in many organisms, including yeasts, plants, frogs, and mammals (2). In these organisms, with the exception of humans, the RFB predominantly inhibits progression of the replication fork in the opposite direction to pre-rRNA transcription (head-on direction), whereas replication in the same direction (codirection) is not obstructed.…”

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The Human RNA Polymerase I Transcription Terminator Complex Acts as a Replication Fork Barrier That Coordinates the Progress of Replication with rRNA Transcription Activity

Akamatsu

Kobayashi

2015

Molecular and Cellular Biology

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In S phase, the replication and transcription of genomic DNA need to accommodate each other, otherwise their machineries collide, with chromosomal instability as a possible consequence. Here, we characterized the human replication fork barrier (RFB) that is present downstream from the 47S pre-rRNA gene (ribosomal DNA [rDNA]). We found that the most proximal transcription terminator, Sal box T1, acts as a polar RFB, while the other, Sal box T4/T5, arrests replication forks bidirectionally. The fork-arresting activity at these sites depends on polymerase I (Pol I) transcription termination factor 1 (TTF-1) and a replisome component, TIMELESS (TIM). We also found that the RFB activity was linked to rDNA copies with hypomethylated CpG and coincided with the time that actively transcribed rRNA genes are replicated. Failed fork arrest at RFB sites led to a slowdown of fork progression moving in the opposite direction to rRNA transcription. Chemical inhibition of transcription counteracted this deceleration of forks, indicating that rRNA transcription impedes replication in the absence of RFB activity. Thus, our results reveal a role of RFB for coordinating the progression of replication and transcription activity in highly transcribed rRNA genes.T he rRNA gene, ribosomal DNA (rDNA), encodes RNA components of ribosomes. In the human genome, there are ϳ400 copies of rDNA encoding the 47S pre-rRNA. These copies are distributed over five clusters of tandemly repeated rDNA on the short arms of acrocentric chromosomes 13, 14, 15, 21, and 22. To meet the vast demand for cellular ribosomes in proliferating human cells, rDNA is heavily transcribed by RNA polymerase I (Pol I). The transcription activity of Pol I fluctuates during the cell cycle; in S phase, the activity is especially vigorous (1). Since both replication and transcription can occur in the same region on the genomic DNA, cells require mechanisms that coordinate these processes.The replication fork barrier (RFB) site near the 3= end of the pre-rRNA coding region has been identified in many organisms, including yeasts, plants, frogs, and mammals (2). In these organisms, with the exception of humans, the RFB predominantly inhibits progression of the replication fork in the opposite direction to pre-rRNA transcription (head-on direction), whereas replication in the same direction (codirection) is not obstructed. Therefore, it is assumed that the RFB arrests the replication fork before it enters the coding region from downstream and thereby prevents the replication fork from colliding with pre-rRNA transcription. In contrast, RFBs in humans are reported to be bidirectional (3).The RFB is formed by a tight complex between certain DNA sequences and proteins that bind to these elements. Fob1 in budding yeast (Saccharomyces cerevisiae) is the best characterized RFB binding protein (4, 5). Deletion of FOB1 allows the replication fork to enter the 35S pre-rRNA coding region from the downstream direction (6, 7). However, when normal numbers of rDNA copies are present, collis...

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The Human RNA Polymerase I Transcription Terminator Complex Acts as a Replication Fork Barrier That Coordinates the Progress of Replication with rRNA Transcription Activity

Akamatsu

Kobayashi

2015

Molecular and Cellular Biology

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Telomere Replication: Solving Multiple End Replication Problems

Bonnell

Pasquier

Wellinger

2021

Front. Cell Dev. Biol.

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Eukaryotic genomes are highly complex and divided into linear chromosomes that require end protection from unwarranted fusions, recombination, and degradation in order to maintain genomic stability. This is accomplished through the conserved specialized nucleoprotein structure of telomeres. Due to the repetitive nature of telomeric DNA, and the unusual terminal structure, namely a protruding single stranded 3′ DNA end, completing telomeric DNA replication in a timely and efficient manner is a challenge. For example, the end replication problem causes a progressive shortening of telomeric DNA at each round of DNA replication, thus telomeres eventually lose their protective capacity. This phenomenon is counteracted by the recruitment and the activation at telomeres of the specialized reverse transcriptase telomerase. Despite the importance of telomerase in providing a mechanism for complete replication of telomeric ends, the majority of telomere replication is in fact carried out by the conventional DNA replication machinery. There is significant evidence demonstrating that progression of replication forks is hampered at chromosomal ends due to telomeric sequences prone to form secondary structures, tightly DNA-bound proteins, and the heterochromatic nature of telomeres. The telomeric loop (t-loop) formed by invasion of the 3′-end into telomeric duplex sequences may also impede the passage of replication fork. Replication fork stalling can lead to fork collapse and DNA breaks, a major cause of genomic instability triggered notably by unwanted repair events. Moreover, at chromosomal ends, unreplicated DNA distal to a stalled fork cannot be rescued by a fork coming from the opposite direction. This highlights the importance of the multiple mechanisms involved in overcoming fork progression obstacles at telomeres. Consequently, numerous factors participate in efficient telomeric DNA duplication by preventing replication fork stalling or promoting the restart of a stalled replication fork at telomeres. In this review, we will discuss difficulties associated with the passage of the replication fork through telomeres in both fission and budding yeasts as well as mammals, highlighting conserved mechanisms implicated in maintaining telomere integrity during replication, thus preserving a stable genome.

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Eukaryotic Replication Barriers: How, Why and Where Forks Stall

Cited by 2 publications

References 156 publications

The Human RNA Polymerase I Transcription Terminator Complex Acts as a Replication Fork Barrier That Coordinates the Progress of Replication with rRNA Transcription Activity

The Human RNA Polymerase I Transcription Terminator Complex Acts as a Replication Fork Barrier That Coordinates the Progress of Replication with rRNA Transcription Activity

Telomere Replication: Solving Multiple End Replication Problems

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