DNA replication-associated lesions: importance in early tumorigenesis and cancer therapy

2007 ◽  
Vol 35 (5) ◽  
pp. 1352-1354 ◽  
Author(s):  
E. Petermann ◽  
T. Helleday
Keyword(s):  
Dna Replication ◽  
Cancer Therapy ◽  
Genetic Instability ◽  
Cellular Response ◽  
Dna Lesions ◽  
Replication Forks ◽  
Associated Lesions ◽  
Repair Pathways

DNA lesions resulting from impaired progression of replication forks are implicated in genetic instability and tumorigenesis. Because the cellular response to these lesions poses an important tumorigenesis barrier, the responsible signalling and repair pathways are often mutated or inactive in tumours. Here, we discuss how such deficiencies can in turn be exploited for cancer therapy.

PCNA on the crossroad of cancer

2009 ◽  
Vol 37 (3) ◽  
pp. 605-613 ◽  
Author(s):  
Ivaylo Stoimenov ◽  
Thomas Helleday
Keyword(s):  
Dna Replication ◽  
Cellular Response ◽  
Cell Cycle Progression ◽  
Tumour Progression ◽  
Dna Lesions ◽  
Nuclear Antigen ◽  
Central Position ◽  
Replication Forks ◽  
Post Translational Modification ◽  
Interaction Partners

Cancer is caused by genetic changes that often arise following failure to accurately replicate the DNA. PCNA (proliferating-cell nuclear antigen) forms a ring around the DNA to facilitate and control DNA replication. Emerging evidence suggests that PCNA is at the very heart of many essential cellular processes, such as DNA replication, repair of DNA damage, chromatin structure maintenance, chromosome segregation and cell-cycle progression. Progression of the DNA replication forks can be blocked by DNA lesions, formed either by endogenous damage or by exogenous agents, for instance anticancer drugs. Cellular response often results in change of PCNA function triggered either by specific post-translational modification of PCNA (i.e. ubiquitylation) or by exchange of its interaction partners. This puts PCNA in a central position in determining the fate of the replication fork. In the present article, we review PCNA modifications and interaction partners, and how those influence the course of events at replication forks, which ultimately determines both tumour progression as well as the outcome of anticancer treatment.

scholarly journals DNA–protein crosslink proteases in genome stability

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Annamaria Ruggiano ◽  
Kristijan Ramadan
Keyword(s):  
Dna Replication ◽  
Cancer Therapy ◽  
Genome Stability ◽  
Dna Lesions ◽  
Protein Component ◽  
Human Diseases ◽  
Direct Link ◽  
The Past ◽  
Protein Crosslinks ◽  
Bulky Dna Lesions

AbstractProteins covalently attached to DNA, also known as DNA–protein crosslinks (DPCs), are common and bulky DNA lesions that interfere with DNA replication, repair, transcription and recombination. Research in the past several years indicates that cells possess dedicated enzymes, known as DPC proteases, which digest the protein component of a DPC. Interestingly, DPC proteases also play a role in proteolysis beside DPC repair, such as in degrading excess histones during DNA replication or controlling DNA replication checkpoints. Here, we discuss the importance of DPC proteases in DNA replication, genome stability and their direct link to human diseases and cancer therapy.

scholarly journals Partial Depletion of Histone H4 Increases Homologous Recombination-Mediated Genetic Instability

2005 ◽  
Vol 25 (4) ◽  
pp. 1526-1536 ◽  
Author(s):  
Félix Prado ◽  
Andrés Aguilera
Keyword(s):  
Dna Replication ◽  
Homologous Recombination ◽  
Dna Sequences ◽  
Genetic Instability ◽  
Yellow Fluorescent Protein ◽  
Dna Lesions ◽  
Micrococcal Nuclease ◽  
Histone H4 ◽  
Nucleosome Assembly ◽  
Partial Depletion

ABSTRACT DNA replication can be a source of genetic instability. Given the tight connection between DNA replication and nucleosome assembly, we analyzed the effect of a partial depletion of histone H4 on genetic instability mediated by homologous recombination. A Saccharomyces cerevisiae strain was constructed in which the expression of histone H4 was driven by the regulated tet promoter. In agreement with defective nucleosome assembly, partial depletion of histone H4 led to subtle changes in plasmid superhelical density and chromatin sensitivity to micrococcal nuclease. Under these conditions, homologous recombination between ectopic DNA sequences was increased 20-fold above the wild-type levels. This hyperrecombination was not associated with either defective repair or transcription but with an accumulation of recombinogenic DNA lesions during the S and G2/M phases, as determined by an increase in the proportion of budded cells containing Rad52-yellow fluorescent protein foci. Consistently, partial depletion of histone H4 caused a delay during the S and G2/M phases. Our results suggest that histone deposition defects lead to the formation of recombinogenic DNA structures during replication that increase genomic instability.

scholarly journals A tough row to hoe: when replication forks encounter DNA damage

2018 ◽  
Vol 46 (6) ◽  
pp. 1643-1651 ◽  
Author(s):  
Darshil R. Patel ◽  
Robert S. Weiss
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Lesions ◽  
Replication Forks ◽  
Brca1 And Brca2 ◽  
Protective Measures ◽  
Checkpoint Proteins ◽  
Ongoing Work ◽  
Damage Response ◽  
Stalled Replication Forks

Eukaryotic cells continuously experience DNA damage that can perturb key molecular processes like DNA replication. DNA replication forks that encounter DNA lesions typically slow and may stall, which can lead to highly detrimental fork collapse if appropriate protective measures are not executed. Stabilization and protection of stalled replication forks ensures the possibility of effective fork restart and prevents genomic instability. Recent efforts from multiple laboratories have highlighted several proteins involved in replication fork remodeling and DNA damage response pathways as key regulators of fork stability. Homologous recombination factors such as RAD51, BRCA1, and BRCA2, along with components of the Fanconi Anemia pathway, are now known to be crucial for stabilizing stalled replication forks and preventing nascent strand degradation. Several checkpoint proteins have additionally been implicated in fork protection. Ongoing work in this area continues to shed light on a sophisticated molecular pathway that balances the action of DNA resection and fork protection to maintain genomic integrity, with important implications for the fate of both normal and malignant cells following replication stress.

scholarly journals DNA polymerase ζ in DNA replication and repair

2019 ◽  
Vol 47 (16) ◽  
pp. 8348-8361 ◽  
Author(s):  
Sara K Martin ◽  
Richard D Wood
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Translesion Synthesis ◽  
Dna Lesions ◽  
Replication Forks ◽  
Dna Replication And Repair ◽  
Radiation Induced ◽  
Break Induced Replication

Abstract Here, we survey the diverse functions of DNA polymerase ζ (pol ζ) in eukaryotes. In mammalian cells, REV3L (3130 residues) is the largest catalytic subunit of the DNA polymerases. The orthologous subunit in yeast is Rev3p. Pol ζ also includes REV7 subunits (encoded by Rev7 in yeast and MAD2L2 in mammalian cells) and two subunits shared with the replicative DNA polymerase, pol δ. Pol ζ is used in response to circumstances that stall DNA replication forks in both yeast and mammalian cells. The best-examined situation is translesion synthesis at sites of covalent DNA lesions such as UV radiation-induced photoproducts. We also highlight recent evidence that uncovers various roles of pol ζ that extend beyond translesion synthesis. For instance, pol ζ is also employed when the replisome operates sub-optimally or at difficult-to-replicate DNA sequences. Pol ζ also participates in repair by microhomology mediated break-induced replication. A rev3 deletion is tolerated in yeast but Rev3l disruption results in embryonic lethality in mice. Inactivation of mammalian Rev3l results in genomic instability and invokes cell death and senescence programs. Targeting of pol ζ function may be a useful strategy in cancer therapy, although chromosomal instability associated with pol ζ deficiency must be considered.

scholarly journals Brc1 Promotes the Focal Accumulation and SUMO Ligase Activity of Smc5-Smc6 during Replication Stress

2018 ◽  
Vol 39 (2) ◽  
Author(s):  
Martina Oravcová ◽  
Mariana C. Gadaleta ◽  
Minghua Nie ◽  
Michael C. Reubens ◽  
Oliver Limbo ◽  
...  
Keyword(s):  
Dna Damage Response ◽  
Genetic Instability ◽  
Genome Stability ◽  
Replication Stress ◽  
Dna Lesions ◽  
Replication Forks ◽  
Response Factors ◽  
Sumo Ligase ◽  
Damage Response ◽  
Key Factor

ABSTRACT As genetic instability drives disease or loss of cell fitness, cellular safeguards have evolved to protect the genome, especially during sensitive cell cycle phases, such as DNA replication. Fission yeast Brc1 has emerged as a key factor in promoting cell survival when replication forks are stalled or collapsed. Brc1 is a multi-BRCT protein that is structurally related to the budding yeast Rtt107 and human PTIP DNA damage response factors, but functional similarities appear limited. Brc1 is a dosage suppressor of a mutation in the essential Smc5-Smc6 genome stability complex and is thought to act in a bypass pathway. In this study, we reveal an unexpectedly intimate connection between Brc1 and Smc5-Smc6 function. Brc1 is required for the accumulation of the Smc5-Smc6 genome stability complex in foci during replication stress and for activation of the intrinsic SUMO ligase activity of the complex by collapsed replication forks. Moreover, we show that the chromatin association and SUMO ligase activity of Smc5-Smc6 require the Nse5-Nse6 heterodimer, explaining how this nonessential cofactor critically supports the DNA repair roles of Smc5-Smc6. We also found that Brc1 interacts with Nse5-Nse6, as well as gamma-H2A, so it can tether Smc5-Smc6 at replicative DNA lesions to promote survival.

scholarly journals The stabilized Pol31–Pol3 interface counteracts Pol32 ablation with differential effects on repair

2021 ◽  
Vol 4 (9) ◽  
pp. e202101138
Author(s):  
Kenji Shimada ◽  
Monika Tsai-Pflugfelder ◽  
Niloofar Davoodi Vijeh Motlagh ◽  
Neda Delgoshaie ◽  
Jeannette Fuchs ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Methyl Methanesulfonate ◽  
Replication Forks ◽  
Differential Effects ◽  
Protein Levels ◽  
Dna Replication And Repair ◽  
Interaction Domains ◽  
Repair Pathways ◽  
Break Induced Replication

DNA polymerase δ, which contains the catalytic subunit, Pol3, Pol31, and Pol32, contributes both to DNA replication and repair. The deletion of pol31 is lethal, and compromising the Pol3–Pol31 interaction domains confers hypersensitivity to cold, hydroxyurea (HU), and methyl methanesulfonate, phenocopying pol32Δ. We have identified alanine-substitutions in pol31 that suppress these deficiencies in pol32Δ cells. We characterize two mutants, pol31-T415A and pol31-W417A, which map to a solvent-exposed loop that mediates Pol31–Pol3 and Pol31–Rev3 interactions. The pol31-T415A substitution compromises binding to the Pol3 CysB domain, whereas Pol31-W417A improves it. Importantly, loss of Pol32, such as pol31-T415A, leads to reduced Pol3 and Pol31 protein levels, which are restored by pol31-W417A. The mutations have differential effects on recovery from acute HU, break-induced replication and trans-lesion synthesis repair pathways. Unlike trans-lesion synthesis and growth on HU, the loss of break-induced replication in pol32Δ cells is not restored by pol31-W417A, highlighting pathway-specific roles for Pol32 in fork-related repair. Intriguingly, CHIP analyses of replication forks on HU showed that pol32Δ and pol31-T415A indirectly destabilize DNA pol α and pol ε at stalled forks.

Sign in / Sign up

Export Citation Format

Share Document