scholarly journals Pathways for maintenance of telomeres and common fragile sites during DNA replication stress

Open Biology ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 180018 ◽  
Author(s):  
Özgün Özer ◽  
Ian D. Hickson
Keyword(s):  
Dna Replication ◽  
Molecular Mechanisms ◽  
Replication Stress ◽  
Fragile Sites ◽  
Repair Synthesis ◽  
Common Fragile Sites ◽  
The Face ◽  
Dna Replication Stress ◽  
Dna Repair Synthesis ◽  
Insight Into

Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently ‘difficult-to-replicate’ nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed ‘mitotic DNA repair synthesis (MiDAS)’, to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.

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.

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 The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3455
Author(s):  
Janne J.M. van Schie ◽  
Job de Lange
Keyword(s):  
Dna Replication ◽  
Sister Chromatid ◽  
Molecular Mechanisms ◽  
Replication Stress ◽  
Sister Chromatid Cohesion ◽  
Key Factors ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Dna Replication Stress ◽  
Subsequent Stabilization

The cohesin complex facilitates faithful chromosome segregation by pairing the sister chromatids after DNA replication until mitosis. In addition, cohesin contributes to proficient and error-free DNA replication. Replisome progression and establishment of sister chromatid cohesion are intimately intertwined processes. Here, we review how the key factors in DNA replication and cohesion establishment cooperate in unperturbed conditions and during DNA replication stress. We discuss the detailed molecular mechanisms of cohesin recruitment and the entrapment of replicated sister chromatids at the replisome, the subsequent stabilization of sister chromatid cohesion via SMC3 acetylation, as well as the role and regulation of cohesin in the response to DNA replication stress.

scholarly journals Targeting DNA Replication Stress for Cancer Therapy

Genes ◽  
2016 ◽  
Vol 7 (8) ◽  
pp. 51 ◽  
Author(s):  
Jun Zhang ◽  
Qun Dai ◽  
Dongkyoo Park ◽  
Xingming Deng
Keyword(s):  
Dna Replication ◽  
Cancer Therapy ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals Targeting the DNA replication stress phenotype of KRAS mutant cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tara Al Zubaidi ◽  
O. H. Fiete Gehrisch ◽  
Marie-Michelle Genois ◽  
Qi Liu ◽  
Shan Lu ◽  
...  
Keyword(s):  
Dna Replication ◽  
Single Molecule ◽  
Replication Stress ◽  
Proton Radiation ◽  
Wild Type ◽  
Cellular Effects ◽  
Proton Treatment ◽  
Dna Replication Stress ◽  
Fork Stalling ◽  
Mutant Cells

AbstractMutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.

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