scholarly journals Recurrent mutations in topoisomerase 2a cause a novel mutator phenotype in human cancers

2020 ◽  
Author(s):  
Arnoud Boot ◽  
Steven G. Rozen
Keyword(s):  
Genome Stability ◽  
Structural Variation ◽  
Cancer Genes ◽  
Genome Maintenance ◽  
Base Pairs ◽  
Mutator Phenotype ◽  
Human Cancers ◽  
Recurrent Mutations ◽  
Activating Mutation ◽  
Topoisomerase 2A

AbstractTopoisomerases are essential for genome stability. Here, we link the p.K743N mutation in topoisomerase TOP2A to a previously undescribed mutator phenotype in human cancers. This phenotype primarily generates a distinctive pattern of duplications of 2 to 4 base pairs and deletions of 6 to 8 base pairs, which we call ID_TOP2A. All tumors carrying the TOP2A p.K743N mutation showed ID_TOP2A, which was absent in all of 12,269 other tumors. We also report evidence of structural variation associated with TOP2A p.K743N. All tumors with ID_TOP2A mutagenesis had several indels in known cancer genes, including frameshift mutations in PTEN and TP53 and an in-frame activating mutation in BRAF. Thus, ID_TOP2A mutagenesis almost certainly contributed to tumorigenesis in these tumors. This is the first report of topoisomerase-associated mutagenesis in human cancers, and sheds further light on TOP2A’s role in genome maintenance. We also postulate that tumors showing ID_TOP2A mutagenesis might be especially sensitive to topoisomerase inhibitors.

scholarly journals Emerging Roles of RAD52 in Genome Maintenance

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1038 ◽  
Author(s):  
Manisha Jalan ◽  
Kyrie S. Olsen ◽  
Simon N. Powell
Keyword(s):  
Genome Stability ◽  
Genome Integrity ◽  
Repair Pathway ◽  
Genome Maintenance ◽  
Knock Out ◽  
Repair Protein ◽  
Attractive Therapeutic Target ◽  
Dna Repair Protein ◽  
Synthetically Lethal ◽  
Knock Out Mice

The maintenance of genome integrity is critical for cell survival. Homologous recombination (HR) is considered the major error-free repair pathway in combatting endogenously generated double-stranded lesions in DNA. Nevertheless, a number of alternative repair pathways have been described as protectors of genome stability, especially in HR-deficient cells. One of the factors that appears to have a role in many of these pathways is human RAD52, a DNA repair protein that was previously considered to be dispensable due to a lack of an observable phenotype in knock-out mice. In later studies, RAD52 deficiency has been shown to be synthetically lethal with defects in BRCA genes, making RAD52 an attractive therapeutic target, particularly in the context of BRCA-deficient tumors.

scholarly journals New Cancer Stochastic Models Involving Both Hereditary and Nonhereditary Cancer Cases: A New Approach

2013 ◽  
Vol 2013 ◽  
pp. 1-19
Author(s):  
Wai-Yuan Tan ◽  
Hong Zhou
Keyword(s):  
Cancer Incidence ◽  
Stochastic Models ◽  
Biological Information ◽  
Cancer Genes ◽  
New Approach ◽  
Human Cancers ◽  
Seer Data ◽  
Sampling Procedures ◽  
And Control ◽  
Better Than

To incorporate biologically observed epidemics into multistage models of carcinogenesis, in this paper we have developed new stochastic models for human cancers. We have further incorporated genetic segregation of cancer genes into these models to derive generalized mixture models for cancer incidence. Based on these models we have developed a generalized Bayesian approach to estimate the parameters and to predict cancer incidence via Gibbs sampling procedures. We have applied these models to fit and analyze the SEER data of human eye cancers from NCI/NIH. Our results indicate that the models not only provide a logical avenue to incorporate biological information but also fit the data much better than other models. These models would not only provide more insights into human cancers but also would provide useful guidance for its prevention and control and for prediction of future cancer cases.

scholarly journals Replisome bypass of a protein-based R-loop block by Pif1

2020 ◽  
Vol 117 (48) ◽  
pp. 30354-30361
Author(s):  
Grant D. Schauer ◽  
Lisanne M. Spenkelink ◽  
Jacob S. Lewis ◽  
Olga Yurieva ◽  
Stefan H. Mueller ◽  
...  
Keyword(s):  
Single Molecule ◽  
Genome Stability ◽  
Genome Instability ◽  
Multiprotein Complex ◽  
Genome Maintenance ◽  
Visualization Technique ◽  
General Displacement ◽  
Maintain Genome Stability ◽  
Protein Blocks

Efficient and faithful replication of the genome is essential to maintain genome stability. Replication is carried out by a multiprotein complex called the replisome, which encounters numerous obstacles to its progression. Failure to bypass these obstacles results in genome instability and may facilitate errors leading to disease. Cells use accessory helicases that help the replisome bypass difficult barriers. All eukaryotes contain the accessory helicase Pif1, which tracks in a 5′–3′ direction on single-stranded DNA and plays a role in genome maintenance processes. Here, we reveal a previously unknown role for Pif1 in replication barrier bypass. We use an in vitro reconstitutedSaccharomyces cerevisiaereplisome to demonstrate that Pif1 enables the replisome to bypass an inactive (i.e., dead) Cas9 (dCas9) R-loop barrier. Interestingly, dCas9 R-loops targeted to either strand are bypassed with similar efficiency. Furthermore, we employed a single-molecule fluorescence visualization technique to show that Pif1 facilitates this bypass by enabling the simultaneous removal of the dCas9 protein and the R-loop. We propose that Pif1 is a general displacement helicase for replication bypass of both R-loops and protein blocks.

scholarly journals NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability

2015 ◽  
Vol 112 (37) ◽  
pp. 11583-11588 ◽  
Author(s):  
Sarah Croessmann ◽  
Hong Yuen Wong ◽  
Daniel J. Zabransky ◽  
David Chu ◽  
Janet Mendonca ◽  
...  
Keyword(s):  
Rna Interference ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Genomic Instability ◽  
Genome Stability ◽  
Suppressor Gene ◽  
Wild Type ◽  
Human Cancers ◽  
Altered Gene ◽  
Interference Studies

The tumor protein 53 (TP53) tumor suppressor gene is the most frequently somatically altered gene in human cancers. Here we show expression of N-Myc down-regulated gene 1 (NDRG1) is induced by p53 during physiologic low proliferative states, and mediates centrosome homeostasis, thus maintaining genome stability. When placed in physiologic low-proliferating conditions, human TP53 null cells fail to increase expression of NDRG1 compared with isogenic wild-type controls and TP53 R248W knockin cells. Overexpression and RNA interference studies demonstrate that NDRG1 regulates centrosome number and amplification. Mechanistically, NDRG1 physically associates with γ-tubulin, a key component of the centrosome, with reduced association in p53 null cells. Strikingly, TP53 homozygous loss was mutually exclusive of NDRG1 overexpression in over 96% of human cancers, supporting the broad applicability of these results. Our study elucidates a mechanism of how TP53 loss leads to abnormal centrosome numbers and genomic instability mediated by NDRG1.

scholarly journals Increased Rates of Genomic Deletions Generated by Mutations in the Yeast Gene Encoding DNA Polymerase δ or by Decreases in the Cellular Levels of DNA Polymerase δ

2000 ◽  
Vol 20 (20) ◽  
pp. 7490-7504 ◽  
Author(s):  
Robert J. Kokoska ◽  
Lela Stefanovic ◽  
Jeremy DeMai ◽  
Thomas D. Petes
Keyword(s):  
Dna Polymerase ◽  
Genome Stability ◽  
Gene Encoding ◽  
Mutator Phenotype ◽  
Genomic Deletions ◽  
Dna Polymerase Δ ◽  
Mutation Avoidance ◽  
Increased Sensitivity

ABSTRACT In Saccharomyces cerevisiae, POL3 encodes the catalytic subunit of DNA polymerase δ. While yeastPOL3 mutant strains that lack the proofreading exonuclease activity of the polymerase have a strong mutator phenotype, little is known regarding the role of other Pol3p domains in mutation avoidance. We identified a number of pol3 mutations in regions outside of the exonuclease domain that have a mutator phenotype, substantially elevating the frequency of deletions. These deletions appear to reflect an increased frequency of DNA polymerase slippage. In addition, we demonstrate that reduction in the level of wild-type DNA polymerase results in a similar mutator phenotype. Lowered levels of DNA polymerase also result in increased sensitivity to the DNA-damaging agent methyl methane sulfonate. We conclude that both the quantity and the quality of DNA polymerase δ is important in ensuring genome stability.

scholarly journals The yeast core spliceosome maintains genome integrity through R-loop prevention and α-tubulin expression

2018 ◽  
Author(s):  
Annie S. Tam ◽  
Veena Mathew ◽  
Tianna S. Sihota ◽  
Anni Zhang ◽  
Peter C. Stirling
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Genome Instability ◽  
Genome Integrity ◽  
Genome Maintenance ◽  
Maintenance Factors ◽  
Spindle Assembly Checkpoint Protein

To achieve genome stability cells must coordinate the action of various DNA transactions including DNA replication, repair, transcription and chromosome segregation. How transcription and RNA processing enable genome stability is only partly understood. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors, and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in a panel yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability. Genome instability in splicing mutants is exacerbated by loss of the spindle-assembly checkpoint protein Mad1. Moreover, removal of the intron from the α-tubulin gene TUB1 restores genome integrity. Thus, while R-loops contribute in some settings, defects in yeast splicing predominantly lead to genome instability through effects on gene expression.

scholarly journals Somatic mutations and genome stability maintenance in clonal coral colonies

2019 ◽  
Author(s):  
Elora H. López ◽  
Stephen R. Palumbi
Keyword(s):  
Loss Of Heterozygosity ◽  
Genome Stability ◽  
Mutation Frequency ◽  
Somatic Mutations ◽  
Somatic Cells ◽  
Genome Maintenance ◽  
Single Nucleotide Variants ◽  
The Face ◽  
Order Of Magnitude ◽  
Multicellular Organisms

AbstractOne challenge for multicellular organisms is maintaining genome stability in the face of mutagens across long life spans. Imperfect genome maintenance leads to mutation accumulation in somatic cells, which is associated with tumors and senescence in vertebrates. Colonial reef-building corals are often large, can live for hundreds of years, rarely develop recognizable tumors, and are thought to convert somatic cells into gamete producers, so they are a pivotal group in which to understand long-term genome maintenance. To measure rates and patterns of somatic mutations, we analyzed transcriptomes from 17-22 branches from each of four Acropora hyacinthus colonies, determined putative single nucleotide variants, and verified them with Sanger resequencing. Unlike for human skin carcinomas, there is no signature of mutations caused by UV damage, indicating either higher efficiency of repair than in vertebrates, or strong sunscreen protection in these shallow water tropical animals. The somatic mutation frequency per nucleotide in A. hyacinthus is on the same order of magnitude (10−7) as noncancerous human somatic cells, and accumulation of mutations with age is similar. Unlike mammals, loss of heterozygosity variants outnumber gain of heterozygosity mutations about 2:1. Although the mutation frequency is similar in mammals and corals, the preponderance of loss of heterozygosity changes and potential selection may reduce the frequency of deleterious mutations in colonial animals like corals. This may limit the deleterious effects of somatic mutations on the coral organism as well as potential offspring.

scholarly journals The Multiple Cellular Roles of SMUG1 in Genome Maintenance and Cancer

2021 ◽  
Author(s):  
Sripriya Raja ◽  
Bennett Van Houten
Keyword(s):  
Genome Stability ◽  
Excision Repair ◽  
Critical Role ◽  
Multiple Roles ◽  
Genome Maintenance ◽  
Uracil Dna Glycosylase ◽  
Damage Recognition ◽  
Base Excision ◽  
Cellular Phenotypes ◽  
Moonlighting Functions

Single-stand selective monofunctional uracil DNA glycosylase 1 (SMUG1) works to remove uracil and certain oxidized bases from DNA during base excision repair (BER). This review provides a historical characterization of SMUG1 and 5-hydroxymethyl-2'-deoxyuridine (5-hmdU) one important substrate of this enzyme. Biochemical and structural analyses provide remarkable insight into the mechanism of this glycosylase revealing SMUG1 has a unique helical wedge which influences damage recognition during repair. Rodent studies suggest that, while SMUG1 shares substrate specificity with another uracil glycosylase UNG2, loss of SMUG1 can have unique cellular phenotypes. This review highlights the multiple roles SMUG1 may play in preserving genome stability, and how the loss of SMUG1 activity may promote cancer. Finally, we discuss recent studies indicating SMUG1 has moonlighting functions beyond BER, playing a critical role in RNA processing including the RNA component of telomerase.

scholarly journals Multiple roles of DNA2 nuclease/helicase in DNA metabolism, genome stability and human diseases

2019 ◽  
Vol 48 (1) ◽  
pp. 16-35 ◽  
Author(s):  
Li Zheng ◽  
Yuan Meng ◽  
Judith L Campbell ◽  
Binghui Shen
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Multiple Roles ◽  
Tumor Promoter ◽  
Genome Maintenance ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Cancer Cell Survival ◽  
Dna Replication And Repair ◽  
End Resection

Abstract DNA2 nuclease/helicase is a structure-specific nuclease, 5′-to-3′ helicase, and DNA-dependent ATPase. It is involved in multiple DNA metabolic pathways, including Okazaki fragment maturation, replication of ‘difficult-to-replicate’ DNA regions, end resection, stalled replication fork processing, and mitochondrial genome maintenance. The participation of DNA2 in these different pathways is regulated by its interactions with distinct groups of DNA replication and repair proteins and by post-translational modifications. These regulatory mechanisms induce its recruitment to specific DNA replication or repair complexes, such as DNA replication and end resection machinery, and stimulate its efficient cleavage of various structures, for example, to remove RNA primers or to produce 3′ overhangs at telomeres or double-strand breaks. Through these versatile activities at replication forks and DNA damage sites, DNA2 functions as both a tumor suppressor and promoter. In normal cells, it suppresses tumorigenesis by maintaining the genomic integrity. Thus, DNA2 mutations or functional deficiency may lead to cancer initiation. However, DNA2 may also function as a tumor promoter, supporting cancer cell survival by counteracting replication stress. Therefore, it may serve as an ideal target to sensitize advanced DNA2-overexpressing cancers to current chemo- and radiotherapy regimens.

Sign in / Sign up

Export Citation Format

Share Document