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Expression of DNA repair gene Ku80 in lymphoid neoplasm
Tsai-Yun Chen1, Jiann-Shiuh Chen, Wu-Chou Su
1Section of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. teresa@mail.ncku.edu.tw
Insights
Ku80, a protein involved in DNA repair, is overexpressed in lymphoid malignancies. High Ku80 levels correlate with poor treatment response in adult acute lymphoblastic leukemia (ALL), suggesting a role in poor prognosis.
Area of Science:
- Molecular Biology
- Oncology
- Immunology
Background:
- Ku80 is a protein heterodimer essential for DNA double-strand break repair and V(D)J recombination.
- Ku80 is implicated as a tumor suppressor gene potentially involved in drug resistance.
- The role of Ku80 in lymphoid malignancies requires further investigation.
Purpose of the Study:
- To determine the role of Ku80 expression in lymphoid malignancies.
- To investigate the correlation between Ku80 expression levels and clinical outcomes in patients with acute lymphoblastic leukemia (ALL).
Main Methods:
- Competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to measure Ku80 expression levels.
- Ku80 transcripts were sequenced to detect potential mutations.
- Expression levels were compared between normal peripheral blood mononuclear cells and malignant cells from patients with ALL and chronic lymphoproliferative disorders.
Main Results:
- No mutations or variants in Ku80 were detected at the RNA level.
- Ku80 expression was significantly increased in adult ALL, pediatric ALL, and chronic lymphoid malignancies compared to controls.
- Higher Ku80 expression in ALL patients was associated with a poorer response to therapy, with only 22% of high expressers achieving durable complete remission versus 62% of low expressers.
Conclusions:
- Ku80 overexpression is observed in lymphoid malignancies.
- Elevated Ku80 levels may indicate a poor prognosis in adult ALL patients.
- Ku80's role in lymphoid malignancy warrants further study, particularly concerning its impact on therapeutic outcomes.
Objectives:
Ku, a heterodimer of KU70 and Ku80 that binds to double-strand DNA breaks (DSBs) and activates the catalytic subunit (DNA-PKcs) when DNA is bound, is essential in DSB repair and V(D)J recombination. Ku80 is a putative tumor suppressor gene that might play an important role in drug resistance. Our aim was to determine the role of Ku80 in lymphoid malignancy.
Patients And Methods:
Competitive reverse transcription-polymerase chain reaction assays were performed and the expression levels of Ku80 were measured in normal peripheral blood mononuclear cells (n = 9) and malignant cells from 25 patients with acute lymphoblastic leukemia (ALL) (14 children, 11 adults), and chronic lymphoproliferative disorders (n = 6). The Ku80 transcripts were sequencing for the possibility of mutation.
Results:
No mutation or Ku80 variant at the RNA level was seen in any patient samples or in the Raji or CCRF-CEM cell lines. In Ku80 expression, 8.8-, 1.9-, and 6.2-fold mean increases were seen in adult, pediatric ALL, and chronic lymphoid malignancies compared with the control. The Ku80 was significantly higher in adult than in pediatric ALL (P = 0.02). The amount of Ku80 expression in ALL was moderately correlated with peripheral white blood cell counts, but not with Ki67 labeling index. High Ku80 expressers (higher than the mean of all patients with ALL) tended to respond poorly to therapy: Only 22% of high Ku80 expressers achieved durable complete remission compared to 62% of low expressers.
Conclusions:
Our study suggests that Ku80 might contribute to generally poor prognoses in adult ALL.
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