scholarly journals Transcription-Replication Collisions and Chromosome Fragility

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Wu ◽  
Jing Na He ◽  
Mengjiao Lan ◽  
Pumin Zhang ◽  
Wai Kit Chu
Keyword(s):  
Cell Division ◽  
Dna Synthesis ◽  
Tumor Development ◽  
Replication Stress ◽  
Fragile Sites ◽  
Repair Pathway ◽  
Entire Genome ◽  
Common Fragile Sites ◽  
Oncogene Activation ◽  
Chromosome Fragility

Accurate replication of the entire genome is critical for cell division and propagation. Certain regions in the genome, such as fragile sites (common fragile sites, rare fragile sites, early replicating fragile sites), rDNA and telomeres, are intrinsically difficult to replicate, especially in the presence of replication stress caused by, for example, oncogene activation during tumor development. Therefore, these regions are particularly prone to deletions and chromosome rearrangements during tumorigenesis, rendering chromosome fragility. Although, the mechanism underlying their “difficult-to-replicate” nature and genomic instability is still not fully understood, accumulating evidence suggests transcription might be a major source of endogenous replication stress (RS) leading to chromosome fragility. Here, we provide an updated overview of how transcription affects chromosome fragility. Furthermore, we will use the well characterized common fragile sites (CFSs) as a model to discuss pathways involved in offsetting transcription-induced RS at these loci with a focus on the recently discovered atypical DNA synthesis repair pathway Mitotic DNA Synthesis (MiDAS).

scholarly journals Common fragile sites are characterised by faulty condensin loading after replication stress

2018 ◽  
Author(s):  
Lora Boteva ◽  
Ryu-Suke Nozawa ◽  
Catherine Naughton ◽  
Kumiko Samejima ◽  
William C Earnshaw ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Fragile Sites ◽  
Molecular Configuration ◽  
Common Fragile Sites ◽  
Molecular Defects ◽  
Specific Manner ◽  
Chromatin Folding

Cells coordinate interphase to mitosis transition but recurrent cytogenetic lesions appear at common fragile sites (CFSs) in a tissue-specific manner following replication stress, marking regions of instability in cancer. Despite such a distinct defect no model fully explains their molecular configuration. We show that CFSs are characterised by impaired chromatin folding manifested as disrupted mitotic structures visible using molecular FISH probes in the presence and absence of replication stress. Chromosome condensation assays reveal that compaction-resistant chromatin lesions persist at CFSs throughout the cell cycle and mitosis. Subsequently cytogenetic and molecular lesions arise due to faulty condensin loading at CFSs, through a defect in condensin I mediated compaction and are coincident with mitotic DNA synthesis (MIDAS). This model suggests that in conditions of exogenous replication stress, aberrant condensin loading leads to molecular defects and CFS formation, concomitantly providing an environment for MIDAS, which, if not resolved, result in chromosome instability.

scholarly journals High-resolution mapping of mitotic DNA synthesis regions and common fragile sites in the human genome through direct sequencing

Cell Research ◽  
2020 ◽  
Vol 30 (11) ◽  
pp. 997-1008 ◽  
Author(s):  
Morgane Macheret ◽  
Rahul Bhowmick ◽  
Katarzyna Sobkowiak ◽  
Laura Padayachy ◽  
Jonathan Mailler ◽  
...  
Keyword(s):  
Dna Replication ◽  
High Resolution ◽  
Dna Synthesis ◽  
Direct Sequencing ◽  
Replication Stress ◽  
Fragile Sites ◽  
Common Fragile Sites ◽  
Dna Replication Stress ◽  
Genomic Regions ◽  
In Cells

Abstract DNA replication stress, a feature of human cancers, often leads to instability at specific genomic loci, such as the common fragile sites (CFSs). Cells experiencing DNA replication stress may also exhibit mitotic DNA synthesis (MiDAS). To understand the physiological function of MiDAS and its relationship to CFSs, we mapped, at high resolution, the genomic sites of MiDAS in cells treated with the DNA polymerase inhibitor aphidicolin. Sites of MiDAS were evident as well-defined peaks that were largely conserved between cell lines and encompassed all known CFSs. The MiDAS peaks mapped within large, transcribed, origin-poor genomic regions. In cells that had been treated with aphidicolin, these regions remained unreplicated even in late S phase; MiDAS then served to complete their replication after the cells entered mitosis. Interestingly, leading and lagging strand synthesis were uncoupled in MiDAS, consistent with MiDAS being a form of break-induced replication, a repair mechanism for collapsed DNA replication forks. Our results provide a better understanding of the mechanisms leading to genomic instability at CFSs and in cancer cells.

scholarly journals Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study

Oncogene ◽  
2007 ◽  
Vol 27 (23) ◽  
pp. 3256-3264 ◽  
Author(s):  
P K Tsantoulis ◽  
A Kotsinas ◽  
P P Sfikakis ◽  
K Evangelou ◽  
M Sideridou ◽  
...  
Keyword(s):  
Replication Stress ◽  
Fragile Sites ◽  
Preneoplastic Lesions ◽  
Common Fragile Sites ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Study

scholarly journals Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D

2013 ◽  
Vol 12 (1) ◽  
pp. 29 ◽  
Author(s):  
Xing Lu ◽  
Swetha Parvathaneni ◽  
Toshifumi Hara ◽  
Ashish Lal ◽  
Sudha Sharma
Keyword(s):  
Replication Stress ◽  
Fragile Sites ◽  
Common Fragile Sites

scholarly journals Molecular Basis for Expression of Common and Rare Fragile Sites

2003 ◽  
Vol 23 (20) ◽  
pp. 7143-7151 ◽  
Author(s):  
Eitan Zlotorynski ◽  
Ayelet Rahat ◽  
Jennifer Skaug ◽  
Neta Ben-Porat ◽  
Efrat Ozeri ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Fragile Site ◽  
Secondary Structures ◽  
Fragile Sites ◽  
Entire Genome ◽  
Common Fragile Sites ◽  
Dna Structures ◽  
Significant Difference ◽  
Minisatellite Repeats ◽  
Genomic Regions

ABSTRACT Fragile sites are specific loci that form gaps, constrictions, and breaks on chromosomes exposed to partial replication stress and are rearranged in tumors. Fragile sites are classified as rare or common, depending on their induction and frequency within the population. The molecular basis of rare fragile sites is associated with expanded repeats capable of adopting unusual non-B DNA structures that can perturb DNA replication. The molecular basis of common fragile sites was unknown. Fragile sites from R-bands are enriched in flexible sequences relative to nonfragile regions from the same chromosomal bands. Here we cloned FRA7E, a common fragile site mapped to a G-band, and revealed a significant difference between its flexibility and that of nonfragile regions mapped to G-bands, similar to the pattern found in R-bands. Thus, in the entire genome, flexible sequences might play a role in the mechanism of fragility. The flexible sequences are composed of interrupted runs of AT-dinucleotides, which have the potential to form secondary structures and hence can affect replication. These sequences show similarity to the AT-rich minisatellite repeats that underlie the fragility of the rare fragile sites FRA16B and FRA10B. We further demonstrate that the normal alleles of FRA16B and FRA10B span the same genomic regions as the common fragile sites FRA16C and FRA10E. Our results suggest that a shared molecular basis, conferred by sequences with a potential to form secondary structures that can perturb replication, may underlie the fragility of rare fragile sites harboring AT-rich minisatellite repeats and aphidicolin-induced common fragile sites.

scholarly journals Visualizing locus-specific sister chromatid exchange reveals differential patterns of replication stress-induced fragile site breakage

Oncogene ◽  
2019 ◽  
Vol 39 (6) ◽  
pp. 1260-1272 ◽  
Author(s):  
Irina Waisertreiger ◽  
Katherine Popovich ◽  
Maya Block ◽  
Krista R. Anderson ◽  
Jacqueline H. Barlow
Keyword(s):  
Dna Repair ◽  
Sister Chromatid ◽  
Sister Chromatid Exchange ◽  
Large Scale ◽  
Fragile Site ◽  
Replication Stress ◽  
Fragile Sites ◽  
Repair Pathway ◽  
Genomic Location ◽  
Pathway Choice

Abstract Chromosomal fragile sites are genomic loci sensitive to replication stress which accumulate high levels of DNA damage, and are frequently mutated in cancers. Fragile site damage is thought to arise from the aberrant repair of spontaneous replication stress, however successful fragile site repair cannot be calculated using existing techniques. Here, we report a new assay measuring recombination-mediated repair at endogenous genomic loci by combining a sister chromatid exchange (SCE) assay with fluorescent in situ hybridization (SCE-FISH). Using SCE-FISH, we find that endogenous and exogenous replication stress generated unrepaired breaks and SCEs at fragile sites. We also find that distinct sources of replication stress induce distinct patterns of breakage: ATR inhibition induces more breaks at early replicating fragile sites (ERFS), while ERFS and late-replicating common fragile sites (CFS) are equally fragile in response to aphidicolin. Furthermore, SCEs were suppressed at fragile sites near centromeres in response to replication stress, suggesting that genomic location influences DNA repair pathway choice. SCE-FISH also measured successful recombination in human primary lymphocytes, and identificed the proto-oncogene BCL2 as a replication stress-induced fragile site. These findings demonstrate that SCE-FISH frequency at fragile sites is a sensitive indicator of replication stress, and that large-scale genome organization influences DNA repair pathway choice.

scholarly journals From R-Loops to G-Quadruplexes: Emerging New Threats for the Replication Fork

2020 ◽  
Vol 21 (4) ◽  
pp. 1506 ◽  
Author(s):  
Antonio Maffia ◽  
Cecilia Ranise ◽  
Simone Sabbioneda
Keyword(s):  
Replication Fork ◽  
Molecular Level ◽  
Replication Stress ◽  
Fragile Sites ◽  
Genome Replication ◽  
Genomic Information ◽  
Hallmarks Of Cancer ◽  
Entire Genome ◽  
G Quadruplex ◽  
The Way

Replicating the entire genome is one of the most complex tasks for all organisms. Research carried out in the last few years has provided us with a clearer picture on how cells preserve genomic information from the numerous insults that may endanger its stability. Different DNA repair pathways, coping with exogenous or endogenous threat, have been dissected at the molecular level. More recently, there has been an increasing interest towards intrinsic obstacles to genome replication, paving the way to a novel view on genomic stability. Indeed, in some cases, the movement of the replication fork can be hindered by the presence of stable DNA: RNA hybrids (R-loops), the folding of G-rich sequences into G-quadruplex structures (G4s) or repetitive elements present at Common Fragile Sites (CFS). Although differing in their nature and in the way they affect the replication fork, all of these obstacles are a source of replication stress. Replication stress is one of the main hallmarks of cancer and its prevention is becoming increasingly important as a target for future chemotherapeutics. Here we will try to summarize how these three obstacles are generated and how the cells handle replication stress upon their encounter. Finally, we will consider their role in cancer and their exploitation in current chemotherapeutic approaches.

scholarly journals Replication Stress Response Links RAD52 to Protecting Common Fragile Sites

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1467 ◽  
Author(s):  
Xiaohua Wu
Keyword(s):  
Mammalian Cells ◽  
Genome Stability ◽  
Replication Stress ◽  
Fragile Sites ◽  
Replication Forks ◽  
Cancer Genes ◽  
Repair Synthesis ◽  
Common Fragile Sites ◽  
Dna Repair Synthesis ◽  
Therapy Target

Rad52 in yeast is a key player in homologous recombination (HR), but mammalian RAD52 is dispensable for HR as shown by the lack of a strong HR phenotype in RAD52-deficient cells and in RAD52 knockout mice. RAD52 function in mammalian cells first emerged with the discovery of its important backup role to BRCA (breast cancer genes) in HR. Recent new evidence further demonstrates that RAD52 possesses multiple activities to cope with replication stress. For example, replication stress-induced DNA repair synthesis in mitosis (MiDAS) and oncogene overexpression-induced DNA replication are dependent on RAD52. RAD52 becomes essential in HR to repair DSBs containing secondary structures, which often arise at collapsed replication forks. RAD52 is also implicated in break-induced replication (BIR) and is found to inhibit excessive fork reversal at stalled replication forks. These various functions of RAD52 to deal with replication stress have been linked to the protection of genome stability at common fragile sites, which are often associated with the DNA breakpoints in cancer. Therefore, RAD52 has important recombination roles under special stress conditions in mammalian cells, and presents as a promising anti-cancer therapy target.

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