scholarly journals Widespread impact of DNA replication on mutational mechanisms in cancer

2017 ◽  
Author(s):  
Marketa Tomkova ◽  
Jakub Tomek ◽  
Skirmantas Kriaucionis ◽  
Benjamin Schuster-Böckler
Keyword(s):  
Dna Replication ◽  
Oxidative Damage ◽  
Esophageal Adenocarcinoma ◽  
Somatic Mutation ◽  
Replication Timing ◽  
Replication Origins ◽  
Mutational Signatures ◽  
Damage Repair ◽  
Cancer Types ◽  
Mutagenic Process

ABSTRACTDNA replication plays an important role in mutagenesis, yet little is known about how it interacts with other mutagenic processes. Here, we use somatic mutation signatures – each representing a mutagenic process – derived from 3056 patients spanning 19 cancer types to quantify the asymmetry of mutational signatures around replication origins and between early and late replicating regions. We observe that 22 out of 29 mutational signatures are significantly impacted by DNA replication. The distinct associations of different signatures with replication timing and direction around origins shed new light on several mutagenic processes, for example suggesting that oxidative damage to the nucleotide pool substantially contributes to the mutational landscape of esophageal adenocarcinoma. Together, our results indicate an involvement of DNA replication and associated damage repair in most mutagenic processes.

scholarly journals Genome-wide mapping of human DNA-replication origins: Levels of transcription at ORC1 sites regulate origin selection and replication timing

2012 ◽  
Vol 23 (1) ◽  
pp. 1-11 ◽  
Author(s):  
G. I. Dellino ◽  
D. Cittaro ◽  
R. Piccioni ◽  
L. Luzi ◽  
S. Banfi ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Timing ◽  
Replication Origins ◽  
Human Dna ◽  
Genome Wide ◽  
Dna Replication Origins

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 Chromatin marks govern mutation landscape of cancer at early stage of progression

2016 ◽  
Author(s):  
Kyungsik Ha ◽  
Hong-Gee Kim ◽  
Hwajin Lee
Keyword(s):  
Barrett’S Esophagus ◽  
Esophageal Adenocarcinoma ◽  
Somatic Mutation ◽  
Cancer Progression ◽  
Barrett's Esophagus ◽  
Epigenetic Changes ◽  
Cell Type ◽  
Cancer Types ◽  
Landscape Establishment ◽  
Time Point

Accumulation of somatic mutations over time leads to tissue abnormalities, such as cancer. Somatic mutation rates vary across the genome in a cell-type specific manner, depending on the types of mutation processes1–7. Although recent studies have identified several determinants relevant to the establishment of the cancer mutation landscape8–13, these studies have yet to propose the major time point at which these factors come into play during cancer progression. Here, we analyzed whole genome sequencing data from two different types of precancerous tissues, monoclonal B-cell lymphocytosis and Barrett’s esophagus, and their matching cancer types along with 423 epigenetic features from normal tissues to determine the critical time point when chromatin features contribute to the formation of the somatic mutation landscape. Our analyses revealed that a subset of cell-of-origin associated chromatin features can explain more than 80% of the regional mutation variance for both types of precancerous tissues, comparable to the variance explained level for the genomes of matching cancer types. In particular, major significant chromatin features explaining the mutation landscape of Barrett’s esophagus and esophageal adenocarcinoma were derived from stomach tissues, indicating that mutation landscape establishment occurs mostly after environment-mediated epigenetic changes during gastric metaplasia. Analyses of the genome of esophageal squamous cell carcinoma tissues demonstrated that the proposed time point for mutation landscape establishment of Barrett’s esophagus and esophageal adenocarcinoma were specific to the occurrence of cell-type shift. Thus, our data suggest that the major time point for the mutation landscape establishment dictated by chromatin features is early in the process of cancer progression, and epigenetic changes due to environmental conditions at early stages can dramatically impact the somatic mutation landscape of cancer.

scholarly journals Loss of histone H3.3 results in DNA replication defects and altered origin dynamics in C. elegans

2019 ◽  
Author(s):  
Maude Strobino ◽  
Joanna M. Wenda ◽  
Florian A. Steiner
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Replication Fork ◽  
Replication Timing ◽  
Embryonic Cell ◽  
Stress Conditions ◽  
Replication Origins ◽  
C Elegans ◽  
Replication Fork Progression ◽  
Histone H3.3

AbstractHistone H3.3 is a replication-independent variant of histone H3 with important roles in development, differentiation and fertility. Here we show that loss of H3.3 results in replication defects in Caenorhabditis elegans embryos. To characterize these defects, we adapt methods to determine replication timing, map replication origins, and examine replication fork progression. Our analysis of the spatiotemporal regulation of DNA replication shows that despite the very rapid embryonic cell cycle, the genome is replicated from early and late firing origins and is partitioned into domains of early and late replication. We find that under temperature stress conditions, additional replication origins become activated. Moreover, loss of H3.3 results in impaired replication fork progression around origins, which is particularly evident at stress-activated origins. These replication defects are accompanied by replication checkpoint activation, a prolonged cell cycle, and increased lethality in checkpoint-compromised embryos. Our comprehensive analysis of DNA replication in C. elegans reveals the genomic location of replication origins and the dynamics of their firing, and uncovers a role of H3.3 in the regulation of replication origins under stress conditions.

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

eLife ◽  
2019 ◽  
Vol 8 ◽  
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

Chromosomal 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. In S. 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.

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