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Related Concept Videos

DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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DNA Damage Can Stall the Cell Cycle02:36

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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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Restarting Stalled Replication Forks02:37

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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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Nucleotide Excision Repair01:38

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DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
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Base Excision Repair01:54

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One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
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Cancer-associated fibroblasts regulate DNA repair in pancreatic cancer through NDRG1-mediated R-loop processing.

Nina Kozlova1,2, Kayla A Cruz3,4,5, Antoine A Ruzette6

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Pancreatic cancer stroma promotes DNA repair through ECM proteins and NDRG1, enhancing tumor survival and chemotherapy resistance. This discovery links tumor microenvironment to genomic instability and replication fork regulation.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Pancreatic ductal adenocarcinomas (PDACs) are aggressive, stroma-rich tumors known for treatment unresponsiveness and rapid relapse after chemotherapy.
  • The tumor stroma, composed of extracellular matrix (ECM) proteins secreted by cancer-associated fibroblasts (CAFs), plays a critical role in PDAC progression.

Purpose of the Study:

  • To investigate the link between CAF-secreted ECM proteins and DNA repair mechanisms in PDAC.
  • To identify key mediators involved in sensing ECM signals and regulating DNA repair.

Main Methods:

  • Utilized molecular biology techniques to identify key mediators.
  • Investigated the role of NDRG1 in sensing ECM signals via adhesion receptors and SGK.
  • Assessed NDRG1's association with replication forks and its function in DNA repair and R-loop resolution.
  • Correlated NDRG1 expression levels with patient survival and chemotherapy response.

Main Results:

  • Identified NDRG1 (N-myc downstream-regulated gene 1) as a crucial mediator linking ECM signals to DNA repair.
  • Demonstrated that NDRG1 physically associates with replication forks, maintains replication, and resolves chemotherapy-induced stalled forks.
  • Showed NDRG1's involvement in reducing R-loops, which are known to cause genomic instability.
  • Found high NDRG1 expression in PDAC tumors, correlating with poor survival and chemotherapy response.

Conclusions:

  • CAF-secreted ECM proteins unexpectedly enhance DNA repair through NDRG1.
  • NDRG1 acts as a key sensor of ECM signals, promoting replication fork homeostasis.
  • This study mechanistically links the tumor stroma to genomic instability regulation via NDRG1 and R-loop control in PDAC.