scholarly journals Medium levels of transcription and replication related chromosomal instability are associated with poor clinical outcome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ataaillah Benhaddou ◽  
Laetitia Gaston ◽  
Gaëlle Pérot ◽  
Nelly Desplat ◽  
Laura Leroy ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Chromosomal Instability ◽  
Holistic Approach ◽  
Instability Index ◽  
Dna Damage And Repair ◽  
Metastatic Relapse ◽  
Dna Elements ◽  
Functional Dna ◽  
Metastatic Risk ◽  
Transcription And Replication

AbstractGenomic instability (GI) influences treatment efficacy and resistance, and an accurate measure of it is lacking. Current measures of GI are based on counts of specific structural variation (SV) and mutational signatures. Here, we present a holistic approach to measuring GI based on the quantification of the steady-state equilibrium between DNA damage and repair as assessed by the residual breakpoints (BP) remaining after repair, irrespective of SV type. We use the notion of Hscore, a BP “hotspotness” magnitude scale, to measure the propensity of genomic structural or functional DNA elements to break more than expected by chance. We then derived new measures of transcription- and replication-associated GI that we call iTRAC (transcription-associated chromosomal instability index) and iRACIN (replication-associated chromosomal instability index). We show that iTRAC and iRACIN are predictive of metastatic relapse in Leiomyosarcoma (LMS) and that they may be combined to form a new classifier called MAGIC (mixed transcription- and replication-associated genomic instability classifier). MAGIC outperforms the gold standards FNCLCC and CINSARC in stratifying metastatic risk in LMS. Furthermore, iTRAC stratifies chemotherapeutic response in LMS. We finally show that this approach is applicable to other cancers.

scholarly journals Metastatic risk stratification of leiomyosarcoma patients using transcription- and replication-associated chromosomal instability mechanisms

2021 ◽  
Author(s):  
Ataaillah Benhaddou ◽  
Laetitia Gaston ◽  
Gaëlle Pérot ◽  
Nelly Desplat ◽  
Laura Leroy ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Chromosomal Instability ◽  
Holistic Approach ◽  
Instability Index ◽  
Dna Damage And Repair ◽  
Metastatic Relapse ◽  
Functional Dna ◽  
Metastatic Risk ◽  
High Level ◽  
Transcription And Replication

AbstractLeiomyosarcoma (LMS) is an aggressive smooth muscle cancer with few therapeutic options. LMSs show a high level of genomic instability (GI) and the mechanisms underlying their oncogenic processes are poorly understood. While the level of GI influences treatment efficacy and resistance, an accurate measure of it is lacking. Current measures of GI are based on counts of specific structural variation (SV) and mutational signatures. Here, we present a holistic approach to measuring GI based on the quantification of the steady-state equilibrium between DNA damage and repair as assessed by the residual breakpoints (BP) remaining after repair, irrespective of SV type. We use the notion of Hscore, a BP “hotspotness” magnitude scale, to measure the propensity of genomic structural or functional DNA elements to break more than expected by chance. We then derived new measures of transcription- and replication-associated GI that we call iTRAC (Transcription-Associated Chromosomal instability index (iTRAC) and iRACIN (Replication-Associated Chromosomal INstability index). We show that iTRAC and iRACIN are predictive of metastatic relapse in LMS and that they may be combined to form a new classifier called MAGIC (Mixed transcription-and replication-Associated Genomic Instability Classifier). MAGIC outperforms the gold standards FNCLCC and CINSARC in stratifying metastatic risk in LMS. Furthermore, iTRAC stratifies chemotherapeutic response in LMS. We finally show that this approach is applicable to other cancers.

scholarly journals Functional equivalency and diversity of cis-acting elements among yeast replication origins.

1997 ◽  
Vol 17 (9) ◽  
pp. 5473-5484 ◽  
Author(s):  
S Lin ◽  
D Kowalski
Keyword(s):  
Origin Recognition Complex ◽  
Common Mechanism ◽  
Dna Unwinding ◽  
Replication Origins ◽  
Yeast Saccharomyces Cerevisiae ◽  
Autonomously Replicating Sequence ◽  
Cis Acting ◽  
Dna Elements ◽  
Functional Dna ◽  
Dna Replication Origins

The DNA replication origins of the yeast Saccharomyces cerevisiae require several short functional elements, most of which are not conserved in sequence. To better characterize ARS305, a replicator from a chromosomal origin, we swapped functional DNA elements of ARS305 with defined elements of ARS1. ARS305 contains elements that are functionally exchangeable with ARS1 A and B1 elements, which are known to bind the origin recognition complex; however, the ARS1 A element differs in that it does not require a 3' box adjacent to the essential autonomously replicating sequence consensus. At the position corresponding to ARS1 B3, ARS305 has a novel element, B4, that can functionally substitute for every type of short element (B1, B2, and B3) in the B domain. Unexpectedly, the replacement of element B4 by ARS1 B3, which binds ABF1p and is known as a replication enhancer, inhibited ARS305 function. ARS305 has no short functional element at or near positions corresponding to the B2 elements in ARS1 and ARS307 but contains an easily unwound region whose functional importance was supported by a broad G+C-rich substitution mutation. Surprisingly, the easily unwound region can functionally substitute for the ARS1 B2 element, even though ARS1 B2 was found to possess a distinct DNA sequence requirement. The functionally conserved B2 element in ARS307 contains a known sequence requirement, and helical stability analysis of linker and minilinker mutations suggested that B2 also contains a DNA unwinding element (DUE). Our findings suggest that yeast replication origins employ a B2 element or a DUE to mediate a common function, DNA unwinding during initiation, although not necessarily through a common mechanism.

Phylogenetic Footprinting to Find Functional DNA Elements

2007 ◽  
pp. 367-380
Author(s):  
Austen R. D. Ganley ◽  
Takehiko Kobayashi
Keyword(s):  
Phylogenetic Footprinting ◽  
Dna Elements ◽  
Functional Dna

scholarly journals Defining functional DNA elements in the human genome

2014 ◽  
Vol 111 (17) ◽  
pp. 6131-6138 ◽  
Author(s):  
M. Kellis ◽  
B. Wold ◽  
M. P. Snyder ◽  
B. E. Bernstein ◽  
A. Kundaje ◽  
...  
Keyword(s):  
Human Genome ◽  
Dna Elements ◽  
Functional Dna

scholarly journals GB3.0: a platform for plant bio-design that connects functional DNA elements with associated biological data

2017 ◽  
pp. gkw1326 ◽  
Author(s):  
Marta Vazquez-Vilar ◽  
Alfredo Quijano-Rubio ◽  
Asun Fernandez-del-Carmen ◽  
Alejandro Sarrion-Perdigones ◽  
Rocio Ochoa-Fernandez ◽  
...  
Keyword(s):  
Biological Data ◽  
Dna Elements ◽  
Functional Dna

scholarly journals Dynamic relocalization of replication origins by Fkh1 requires execution of DDK function and Cdc45 loading at origins

2019 ◽  
Author(s):  
Haiyang Zhang ◽  
Meghan V. Petrie ◽  
Yiwei He ◽  
Jared M. Peace ◽  
Irene E. Chiolo ◽  
...  
Keyword(s):  
Dna Replication ◽  
Spatial Organization ◽  
Nuclear Periphery ◽  
Replication Timing ◽  
G1 Phase ◽  
Replication Origins ◽  
Chromosomal Dna ◽  
Dna Elements ◽  
Functional Dna ◽  
High Level

ABSTRACTChromosomal DNA elements are organized into spatial domains within the eukaryotic nucleus. Sites undergoing DNA replication, high-level transcription, and repair of double-strand breaks coalesce into foci, although the significance and mechanisms giving rise to these dynamic structures are poorly understood. InS. cerevisiae, replication origins occupy characteristic subnuclear localizations that anticipate their initiation timing during S phase. Here, we link localization of replication origins in G1 phase with Fkh1 activity, which is required for their early replication timing. Using a Fkh1-dependent origin relocalization assay, we determine that execution of Dbf4-dependent kinase function, including Cdc45 loading, results in dynamic relocalization of a replication origin from the nuclear periphery to the interior in G1 phase. Origin mobility increases substantially with Fkh1-driven relocalization. These findings provide novel molecular insight into the mechanisms that govern dynamics and spatial organization of DNA replication origins and possibly other functional DNA elements.

scholarly journals Mitotic systemic genomic instability in yeast

2017 ◽  
Author(s):  
Nadia M. V. Sampaio ◽  
Aline Rodrigues-Prause ◽  
V. P. Ajith ◽  
Theodore M. Gurol ◽  
Mary J. Chapman ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Loss Of Heterozygosity ◽  
Chromosomal Instability ◽  
Experimental Approach ◽  
Human Cancer ◽  
Chromosomal Rearrangements ◽  
Point Mutations ◽  
Genomic Variation ◽  
Genomic Disorder ◽  
Structural Genomic

ABSTRACTConventional models of genome evolution generally include the assumption that mutations accumulate gradually and independently over time. We characterized the occurrence of sudden spikes in the accumulation of genome-wide loss-of-heterozygosity (LOH) inSaccharomyces cerevisiae, suggesting the existence of a mitotic systemic genomic instability process (mitSGI). We characterized the emergence of a rough colony morphology phenotype resulting from an LOH event spanning a specific locus (ACE2/ace2-A7). Surprisingly, half of the clones analyzed also carried unselected secondary LOH tracts elsewhere in their genomes. The number of secondary LOH tracts detected was 20-fold higher than expected assuming independence between mutational events. Secondary LOH tracts were not detected in control clones without a primary selected LOH event. We then measured the rates of single and double LOH at different chromosome pairs and found that coincident LOH accumulated at rates 30-100 fold higher than expected if the two underlying single LOH events occurred independently. These results were consistent between two different strain backgrounds, and in mutant strains incapable of entering meiosis. Our results indicate that a subset of mitotic cells within a population experience systemic genomic instability episodes, resulting in multiple chromosomal rearrangements over one or few generations. They are reminiscent of early reports from the classic yeast genetics literature, as well as recent studies in humans, both in the cancer and genomic disorder contexts, all of which challenge the idea of gradual accumulation of structural genomic variation. Our experimental approach provides a model to further dissect the fundamental mechanisms responsible for mitSGI.SIGNIFICANCE STATEMENTPoint mutations and alterations in chromosome structure are generally thought to accumulate gradually and independently over many generations. Here, we combined complementary genetic approaches in budding yeast to track the appearance of chromosomal changes resulting in loss-of-heterozygosity (LOH). Contrary to expectations, our results provided evidence for the occurrence of non-independent accumulation of multiple LOH events over one or a few cell generations. These results are analogous to recent reports of bursts of chromosomal instability in humans. Our experimental approach provides a framework to further dissect the fundamental mechanisms underlying systemic chromosomal instability processes, including in the human cancer and genomic disorder contexts.

scholarly journals Holistic View on Cell Survival and DNA Damage: How Model-Based Data Analysis Supports Exploration of Dynamics in Biological Systems

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Mathias S. Weyland ◽  
Pauline Thumser-Henner ◽  
Katarzyna J. Nytko ◽  
Carla Rohrer Bley ◽  
Simone Ulzega ◽  
...  
Keyword(s):  
Dna Damage ◽  
Model Calibration ◽  
Biological Effects ◽  
Holistic Approach ◽  
Model Parameters ◽  
Calibration Model ◽  
Sources Of Information ◽  
Dna Damage And Repair ◽  
Holistic View ◽  
Successful Model

In this work, a method is established to calibrate a model that describes the basic dynamics of DNA damage and repair. The model can be used to extend planning for radiotherapy and hyperthermia in order to include the biological effects. In contrast to “syntactic” models (e.g., describing molecular kinetics), the model used here describes radiobiological semantics, resulting in a more powerful model but also in a far more challenging calibration. Model calibration is attempted from clonogenic assay data (doses of 0–6 Gy) and from time-resolved comet assay data obtained within 6 h after irradiation with 6 Gy. It is demonstrated that either of those two sources of information alone is insufficient for successful model calibration, and that both sources of information combined in a holistic approach are necessary to find viable model parameters. Approximate Bayesian computation (ABC) with simulated annealing is used for parameter search, revealing two aspects that are beneficial to resolving the calibration problem: (1) assessing posterior parameter distributions instead of point-estimates and (2) combining calibration runs from different assays by joining posterior distributions instead of running a single calibration run with a combined, computationally very expensive objective function.

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