Y-family DNA polymerases respond to DNA damage-independent inhibition of replication fork progression

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.

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

Nature Communications ◽

10.1038/s41467-020-19674-0 ◽

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.

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

Scientific Reports ◽

10.1038/srep03277 ◽

2013 ◽

Vol 3 (1) ◽

Cited By ~ 11

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

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

Oncogene ◽

10.1038/sj.onc.1209624 ◽

2006 ◽

Vol 25 (44) ◽

pp. 5921-5932 ◽

Cited By ~ 27

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

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Faculty Opinions recommendation of Replication fork progression during re-replication requires the DNA damage checkpoint and double-strand break repair.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725540496.793507742 ◽

2015 ◽

Author(s):

Jeff Sekelsky

Keyword(s):

Dna Damage ◽

Replication Fork ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Dna Damage Checkpoint ◽

Replication Fork Progression ◽

Break Repair

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Checkpoint regulation of replication forks: global or local?

Biochemical Society Transactions ◽

10.1042/bst20130197 ◽

2013 ◽

Vol 41 (6) ◽

pp. 1701-1705 ◽

Cited By ~ 8

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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Replication fork dynamics and the DNA damage response

Biochemical Journal ◽

10.1042/bj20112100 ◽

2012 ◽

Vol 443 (1) ◽

pp. 13-26 ◽

Cited By ~ 77

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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Mechanisms for Maintaining Eukaryotic Replisome Progression in the Presence of DNA Damage

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.712971 ◽

2021 ◽

Vol 8 ◽

Author(s):

Thomas A. Guilliam

Keyword(s):

Dna Damage ◽

Single Molecule ◽

Replication Fork ◽

Genome Stability ◽

Genome Duplication ◽

Damage Tolerance ◽

Tolerance Mechanisms ◽

Dna Damage Tolerance ◽

Replication Fork Progression ◽

The Impact

The eukaryotic replisome coordinates template unwinding and nascent-strand synthesis to drive DNA replication fork progression and complete efficient genome duplication. During its advancement along the parental template, each replisome may encounter an array of obstacles including damaged and structured DNA that impede its progression and threaten genome stability. A number of mechanisms exist to permit replisomes to overcome such obstacles, maintain their progression, and prevent fork collapse. A combination of recent advances in structural, biochemical, and single-molecule approaches have illuminated the architecture of the replisome during unperturbed replication, rationalised the impact of impediments to fork progression, and enhanced our understanding of DNA damage tolerance mechanisms and their regulation. This review focusses on these studies to provide an updated overview of the mechanisms that support replisomes to maintain their progression on an imperfect template.

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