scholarly journals DNA polymerase η modulates replication fork progression and DNA damage responses in platinum-treated human cells

2013 ◽  
Vol 3 (1) ◽  
Author(s):  
Anna M. Sokol ◽  
Séverine Cruet-Hennequart ◽  
Philippe Pasero ◽  
Michael P. Carty
Keyword(s):  
Dna Damage ◽  
Dna Polymerase ◽  
Replication Fork ◽  
Human Cells ◽  
Replication Fork Progression ◽  
Dna Damage Responses

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 Active Site Mutations in Mammalian DNA Polymerase δ Alter Accuracy and Replication Fork Progression

2010 ◽  
Vol 285 (42) ◽  
pp. 32264-32272 ◽  
Author(s):  
Michael W. Schmitt ◽  
Ranga N. Venkatesan ◽  
Marie-Jeanne Pillaire ◽  
Jean-Sébastien Hoffmann ◽  
Julia M. Sidorova ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Active Site ◽  
Replication Fork ◽  
Dna Polymerase Δ ◽  
Replication Fork Progression ◽  
Active Site Mutations

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 Human Mcm10 Regulates the Catalytic Subunit of DNA Polymerase-α and Prevents DNA Damage during Replication

2007 ◽  
Vol 18 (10) ◽  
pp. 4085-4095 ◽  
Author(s):  
Sharbani Chattopadhyay ◽  
Anja-Katrin Bielinsky
Keyword(s):  
Dna Damage ◽  
Dna Polymerase ◽  
S Phase ◽  
Human Cells ◽  
Replication Initiation ◽  
Catalytic Subunit ◽  
Drosophila Embryo ◽  
Minichromosome Maintenance ◽  
Α Subunit ◽  
Phase Entry

In Saccharomyces cerevisiae, minichromosome maintenance protein (Mcm) 10 interacts with DNA polymerase (pol)-α and functions as a nuclear chaperone for the catalytic subunit, which is rapidly degraded in the absence of Mcm10. We report here that the interaction between Mcm10 and pol-α is conserved in human cells. We used a small interfering RNA-based approach to deplete Mcm10 in HeLa cells, and we observed that the catalytic subunit of pol-α, p180, was degraded with similar kinetics as Mcm10, whereas the regulatory pol-α subunit, p68, remained unaffected. Simultaneous loss of Mcm10 and p180 inhibited S phase entry and led to an accumulation of already replicating cells in late S/G2 as a result of DNA damage, which triggered apoptosis in a subpopulation of cells. These phenotypes differed considerably from analogous studies in Drosophila embryo cells that did not exhibit a similar arrest. To further dissect the roles of Mcm10 and p180 in human cells, we depleted p180 alone and observed a significant delay in S phase entry and fork progression but little effect on cell viability. These results argue that cells can tolerate low levels of p180 as long as Mcm10 is present to “recycle” it. Thus, human Mcm10 regulates both replication initiation and elongation and maintains genome integrity.

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.

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