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Related Concept Videos

Translesion DNA Polymerases02:10

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
Replication in Eukaryotes01:29

Replication in Eukaryotes

In eukaryotic cells, DNA replication is highly conserved and tightly regulated. Multiple linear chromosomes must be duplicated with high fidelity before cell division, so there are many proteins that fulfill specialized roles in the replication process. Replication occurs in three phases: initiation, elongation, and termination, and ends with two complete sets of chromosomes in the nucleus.
Many Proteins Orchestrate Replication at the Origin
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DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

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...
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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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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Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
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Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence.

Eli S Williams1, Rebekah Klingler, Brian Ponnaiya

  • 1Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523-1618, USA.

Cancer Research
|February 27, 2009
PubMed
Summary
This summary is machine-generated.

Cells deficient in DNA-dependent protein kinase (DNA-PKcs) have uncapped telomeres that are mistaken for DNA double-strand breaks (DSBs), leading to genomic instability and potentially cancer. This DNA repair defect links genetic susceptibility and radiation exposure to breast cancer risk.

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Area of Science:

  • Cellular biology
  • DNA repair mechanisms
  • Genomics

Background:

  • Distinguishing telomeres from DNA double-strand breaks (DSBs) is crucial for genome stability.
  • The nonhomologous end-joining (NHEJ) pathway, particularly DNA-dependent protein kinase (DNA-PK), plays a role in telomere maintenance.
  • Dysfunctional telomeres can lead to genomic instability and disease.

Purpose of the Study:

  • To investigate the consequences of uncapped telomeres in cells lacking DNA-PKcs.
  • To elucidate the mechanisms by which uncapped telomeres are processed as DSBs.
  • To explore the link between DNA-PKcs deficiency, telomere dysfunction, and cancer susceptibility.

Main Methods:

  • Characterization of uncapped telomeres in DNA-PKcs-deficient cells.
  • Analysis of telomere-telomere and telomere-DSB fusion events.
  • Investigation of DNA-PKcs phosphorylation and its role in telomere processing.
  • Examination of telomere status in BALB/c mice with reduced DNA-PKcs activity.

Main Results:

  • Uncapped telomeres in DNA-PKcs-deficient cells are recognized and processed as DSBs.
  • These dysfunctional telomeres undergo spontaneous and radiation-induced fusion events.
  • Phosphorylation of DNA-PKcs (Thr-2609 cluster) is critical for proper telomere end-processing.
  • Ligase IV is required for uncapped telomere fusion.
  • BALB/c mice with reduced DNA-PKcs exhibit radiosensitivity and mammary cancer susceptibility.

Conclusions:

  • Uncapped telomeres in DNA-PKcs-deficient cells contribute to genomic instability.
  • Mechanistic links exist between dysfunctional telomeres, radiation sensitivity, and breast cancer.
  • Genetic susceptibility and environmental factors interact to drive carcinogenesis through telomere dysfunction.