scholarly journals SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability

2018 ◽  
Vol 46 (18) ◽  
pp. 9891-9891 ◽  
Author(s):  
Kim Hjorth-Jensen ◽  
Apolinar Maya-Mendoza ◽  
Nanna Dalgaard ◽  
Jón O Sigurðsson ◽  
Jiri Bartek ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Replication Stress ◽  
Transcriptional Expression ◽  
Replication Factors

scholarly journals SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability

2018 ◽  
Vol 46 (18) ◽  
pp. 9484-9495 ◽  
Author(s):  
Kim Hjorth-Jensen ◽  
Apolinar Maya-Mendoza ◽  
Nanna Dalgaard ◽  
Jón O Sigurðsson ◽  
Jiri Bartek ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Replication Stress ◽  
Transcriptional Expression ◽  
Replication Factors

scholarly journals MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Benjamin B. Morris ◽  
Nolan A. Wages ◽  
Patrick A. Grant ◽  
P. Todd Stukenberg ◽  
Ryan D. Gentzler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Transcription Factor ◽  
Lung Adenocarcinoma ◽  
Genomic Instability ◽  
Replication Stress ◽  
Omics Data ◽  
Repair Pathways ◽  
Lung Adenocarcinomas

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

scholarly journals The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009868
Author(s):  
Irena Bočkaj ◽  
Tosca E. I. Martini ◽  
Eduardo S. de Camargo Magalhães ◽  
Petra L. Bakker ◽  
Tiny G. J. Meeuwsen-de Boer ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genomic Instability ◽  
High Grade Glioma ◽  
Replication Stress ◽  
Nuclear Body ◽  
Tumor Formation ◽  
High Grade ◽  
Mitotic Abnormalities ◽  
Replication Factors

While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation of the chromatin landscape, the exact mechanisms driving tumor formation remain poorly understood. Since H3.3 mutant gliomas also exhibit high levels of copy number alterations, we set out to address if the H3.3K27M oncohistone leads to destabilization of the genome. Hereto, we established a cell culture model allowing inducible H3.3K27M expression and observed an increase in mitotic abnormalities. We also found enhanced interaction of DNA replication factors with H3.3K27M during mitosis, indicating replication defects. Further functional analyses revealed increased genomic instability upon replication stress, as represented by mitotic bulky and ultrafine DNA bridges. This co-occurred with suboptimal 53BP1 nuclear body formation after mitosis in vitro, and in human glioma. Finally, we observed a decrease in ultrafine DNA bridges following deletion of the K27M mutant H3F3A allele in primary high-grade glioma cells. Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development.

scholarly journals DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects

2021 ◽  
Vol 118 (17) ◽  
pp. e2024258118
Author(s):  
Nanda Kumar Jegadesan ◽  
Dana Branzei
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Drug Hypersensitivity ◽  
Replication Stress ◽  
Strand Break ◽  
Parp Inhibitors ◽  
Dna Helicase ◽  
Brca1 And Brca2 ◽  
Focus Formation ◽  
Chemotherapy Drug

DDX11 encodes an iron–sulfur cluster DNA helicase required for development, mutated, and overexpressed in cancers. Here, we show that loss of DDX11 causes replication stress and sensitizes cancer cells to DNA damaging agents, including poly ADP ribose polymerase (PARP) inhibitors and platinum drugs. We find that DDX11 helicase activity prevents chemotherapy drug hypersensitivity and accumulation of DNA damage. Mechanistically, DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in manners nonredundant with BRCA1 and BRCA2. As a result, DDX11 down-regulation aggravates the chemotherapeutic sensitivity of BRCA1/2-mutated cancers and resensitizes chemotherapy drug–resistant BRCA1/2-mutated cancer cells that regained homologous recombination proficiency. The results further indicate that DDX11 facilitates recombination repair by assisting double strand break resection and the loading of both RPA and RAD51 on single-stranded DNA substrates. We propose DDX11 as a potential target in cancers by creating pharmacologically exploitable DNA repair vulnerabilities.

scholarly journals A new role for a tumor-suppressing protein

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Jeremy S Setton ◽  
Simon N Powell
Keyword(s):  
Dna Repair ◽  
Stress Response ◽  
Replication Stress ◽  
Repair Process ◽  
Protein P53

In addition to its role in preventing tumors, the protein p53 appears to participate in a DNA repair process known as the replication-stress response.

scholarly journals Collaboration in the actions of Brh2 with resolving functions during DNA repair and replication stress in Ustilago maydis

DNA Repair ◽  
2018 ◽  
Vol 63 ◽  
pp. 47-55
Author(s):  
Milorad Kojic ◽  
Mira Milisavljevic ◽  
William K. Holloman
Keyword(s):  
Dna Repair ◽  
Replication Stress ◽  
Ustilago Maydis

scholarly journals Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

Oncogenesis ◽  
2020 ◽  
Vol 9 (10) ◽  
Author(s):  
Yannick P. Kok ◽  
Sergi Guerrero Llobet ◽  
Pepijn M. Schoonen ◽  
Marieke Everts ◽  
Arkajyoti Bhattacharya ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Checkpoint Inhibitors ◽  
Replication Stress ◽  
Underlying Mechanism ◽  
Dna Lesions ◽  
Mitotic Catastrophe ◽  
Replication Checkpoint ◽  
Cyclin E1 ◽  
Checkpoint Kinases ◽  
Increased Sensitivity

Abstract Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases. We modeled oncogene-induced replication stress using inducible expression of Cyclin E1 or Cdc25A in non-transformed RPE-1 cells, either in a TP53 wild-type or TP53-mutant background. DNA fiber analysis showed Cyclin E1 or Cdc25A overexpression to slow replication speed. The resulting replication-derived DNA lesions were transmitted into mitosis causing chromosome segregation defects. Single cell sequencing revealed that replication stress and mitotic defects upon Cyclin E1 or Cdc25A overexpression resulted in genomic instability. ATR or WEE1 inhibition exacerbated the mitotic aberrancies induced by Cyclin E1 or Cdc25A overexpression, and caused cytotoxicity. Both these phenotypes were exacerbated upon p53 inactivation. Conversely, downregulation of Cyclin E1 rescued both replication kinetics, as well as sensitivity to ATR and WEE1 inhibitors. Taken together, Cyclin E1 or Cdc25A-induced replication stress leads to mitotic segregation defects and genomic instability. These mitotic defects are exacerbated by inhibition of ATR or WEE1 and therefore point to mitotic catastrophe as an underlying mechanism. Importantly, our data suggest that Cyclin E1 overexpression can be used to select patients for treatment with replication checkpoint inhibitors.

scholarly journals Distinct DNA repair pathways cause genomic instability at alternative DNA structures

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jennifer A. McKinney ◽  
Guliang Wang ◽  
Anirban Mukherjee ◽  
Laura Christensen ◽  
Sai H. Sankara Subramanian ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Dna Structures ◽  
Repair Pathways

Genomic Instability and DNA Repair

2007 ◽  
Author(s):  
Sarantis Gagos
Keyword(s):  
Dna Repair ◽  
Genomic Instability
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