scholarly journals The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest

Cell Cycle ◽  
2008 ◽  
Vol 7 (6) ◽  
pp. 796-807 ◽  
Author(s):  
Julia M. Sidorova ◽  
Nianzhen Li ◽  
Albert Folch ◽  
Raymond J. Monnat, Jr.
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
Recq Helicase ◽  
Replication Fork Progression ◽  
Replication Fork Arrest

scholarly journals A transcription-based mechanism for oncogenic β-catenin-induced lethality in BRCA1/2-deficient cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rebecca A. Dagg ◽  
Gijs Zonderland ◽  
Emilia Puig Lombardi ◽  
Giacomo G. Rossetti ◽  
Florian J. Groelly ◽  
...  
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
High Throughput Sequencing ◽  
Germline Mutations ◽  
Cdk Inhibitor ◽  
Rna Seq ◽  
Gene Encoding ◽  
Origin Firing ◽  
Replication Fork Progression ◽  
Transcriptional Alterations

AbstractBRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers. High-throughput sequencing of tumour genomes revealed that oncogene amplification and BRCA1/2 mutations are mutually exclusive in cancer, however the molecular mechanism underlying this incompatibility remains unknown. Here, we report that activation of β-catenin, an oncogene of the WNT signalling pathway, inhibits proliferation of BRCA1/2-deficient cells. RNA-seq analyses revealed β-catenin-induced discrete transcriptome alterations in BRCA2-deficient cells, including suppression of CDKN1A gene encoding the CDK inhibitor p21. This accelerates G1/S transition, triggering illegitimate origin firing and DNA damage. In addition, β-catenin activation accelerates replication fork progression in BRCA2-deficient cells, which is critically dependent on p21 downregulation. Importantly, we find that upregulated p21 expression is essential for the survival of BRCA2-deficient cells and tumours. Thus, our work demonstrates that β-catenin toxicity in cancer cells with compromised BRCA1/2 function is driven by transcriptional alterations that cause aberrant replication and inflict DNA damage.

scholarly journals Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessandro Cicconi ◽  
Rekha Rai ◽  
Xuexue Xiong ◽  
Cayla Broton ◽  
Amer Al-Hiyasat ◽  
...  
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
Clinical Feature ◽  
Replication Forks ◽  
Primary Microcephaly ◽  
Dna Damage And Repair ◽  
Homology Directed Repair ◽  
Replication Fork Progression ◽  
Telomere Binding Protein ◽  
Telomere Replication

AbstractTelomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1–TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.

scholarly journals Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest

2013 ◽  
Vol 33 (16) ◽  
pp. 3390-3390
Author(s):  
Mayank Singh ◽  
Clayton R. Hunt ◽  
Raj K. Pandita ◽  
Rakesh Kumar ◽  
Chin-Rang Yang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
Lamin A ◽  
Replication Fork Arrest

scholarly journals Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

Oncogene ◽  
2006 ◽  
Vol 25 (44) ◽  
pp. 5921-5932 ◽  
Author(s):  
T Shimura ◽  
M Toyoshima ◽  
S K Adiga ◽  
T Kunoh ◽  
H Nagai ◽  
...  
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
Low Dose ◽  
S Phase ◽  
Dna Damage Checkpoint ◽  
Replication Fork Progression

scholarly journals Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 19 ◽  
Author(s):  
Elisa Coluzzi ◽  
Stefano Leone ◽  
Antonella Sgura
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Replication Fork ◽  
Oxidative Dna Damage ◽  
Telomere Dysfunction ◽  
Loop Formation ◽  
Strand Breaks ◽  
Hydrogen Peroxide Treatment ◽  
Primary Fibroblasts ◽  
Replication Fork Arrest

Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this study, we wanted to understand the mechanisms by which oxidative damage causes telomere dysfunction and senescence in human primary fibroblasts. After acute oxidative stress at telomeres, our data demonstrated a reduction in TRF1 and TRF2, which are involved in proper telomere replication and T-loop formation, respectively. Furthermore, we observed a higher level of γH2AX with respect to 53BP1 at telomeres, suggesting a telomeric replication fork stall rather than double-strand breaks. To confirm this finding, we studied the replication of telomeres by Chromosome Orientation-FISH (CO-FISH). The data obtained show an increase in unreplicated telomeres after hydrogen peroxide treatment, corroborating the idea that the presence of 8-oxoG can induce replication fork arrest at telomeres. Lastly, we analyzed the H3K9me3 histone mark after oxidative stress at telomeres, and our results showed an increase of this marker, most likely inducing the heterochromatinization of telomeres. These results suggest that 8-oxoG is fundamental in oxidative stress-induced telomeric damage, principally causing replication fork arrest.

scholarly journals Checkpoint regulation of replication forks: global or local?

2013 ◽  
Vol 41 (6) ◽  
pp. 1701-1705 ◽  
Author(s):  
Divya Ramalingam Iyer ◽  
Nicholas Rhind
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
S Phase ◽  
Cell Cycle Checkpoints ◽  
Dna Damage Checkpoint ◽  
Replication Forks ◽  
Origin Firing ◽  
Replication Fork Progression ◽  
Late Origin ◽  
Stalled Replication Forks

Cell-cycle checkpoints are generally global in nature: one unattached kinetochore prevents the segregation of all chromosomes; stalled replication forks inhibit late origin firing throughout the genome. A potential exception to this rule is the regulation of replication fork progression by the S-phase DNA damage checkpoint. In this case, it is possible that the checkpoint is global, and it slows all replication forks in the genome. However, it is also possible that the checkpoint acts locally at sites of DNA damage, and only slows those forks that encounter DNA damage. Whether the checkpoint regulates forks globally or locally has important mechanistic implications for how replication forks deal with damaged DNA during S-phase.

scholarly journals Replication fork dynamics and the DNA damage response

2012 ◽  
Vol 443 (1) ◽  
pp. 13-26 ◽  
Author(s):  
Rebecca M. Jones ◽  
Eva Petermann
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Replication Fork ◽  
Molecular Mechanisms ◽  
S Phase ◽  
Replication Initiation ◽  
Developmental Defects ◽  
Replication Fork Progression ◽  
Damage Response

Prevention and repair of DNA damage is essential for maintenance of genomic stability and cell survival. DNA replication during S-phase can be a source of DNA damage if endogenous or exogenous stresses impair the progression of replication forks. It has become increasingly clear that DNA-damage-response pathways do not only respond to the presence of damaged DNA, but also modulate DNA replication dynamics to prevent DNA damage formation during S-phase. Such observations may help explain the developmental defects or cancer predisposition caused by mutations in DNA-damage-response genes. The present review focuses on molecular mechanisms by which DNA-damage-response pathways control and promote replication dynamics in vertebrate cells. In particular, DNA damage pathways contribute to proper replication by regulating replication initiation, stabilizing transiently stalled forks, promoting replication restart and facilitating fork movement on difficult-to-replicate templates. If replication fork progression fails to be rescued, this may lead to DNA damage and genomic instability via nuclease processing of aberrant fork structures or incomplete sister chromatid separation during mitosis.

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