Related Experiment Video
Updated: Jun 18, 2026
13:10
Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
Published on: June 9, 2017
ATM regulates a RASSF1A-dependent DNA damage response.
Garth Hamilton1, Karen S Yee, Simon Scrace
1Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
Current Biology : CB
|December 8, 2009
Summary
Epigenetic silencing of RASSF1A or mutations disabling its ATM phosphorylation site are frequent in cancer. This disrupts a novel DNA damage pathway, reducing apoptosis and therapy response.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Hypermethylation of the RASSF1 promoter is common in cancer, leading to RASSF1A loss and reduced DNA-damaging therapy response.
- RASSF1A normally promotes apoptosis via MST2/LATS1 kinases, stabilizing the YAP1/p73 complex.
Purpose of the Study:
- To identify a novel DNA damage signaling pathway involving RASSF1A.
- To investigate the role of ATM in RASSF1A activation and its implications in cancer.
Main Methods:
- Investigated the link between DNA damage signaling and RASSF1A using cell lines.
- Analyzed RASSF1A phosphorylation by ATM and its effect on downstream signaling.
- Examined RASSF1A polymorphisms in tumor cell lines and their association with therapy resistance.
Main Results:
- DNA damage induces RASSF1A phosphorylation by ATM at Ser131, activating MST2/LATS1 and stabilizing p73.
- Lung and ovarian tumors with retained RASSF1A expression often have Ser131 polymorphisms.
- The S131F polymorphism confers resistance to DNA-damaging agents.
Conclusions:
- A novel ATM-RASSF1A DNA damage pathway exists and is frequently disrupted in cancer.
- Disruption occurs via RASSF1 epigenetic silencing or ATM phosphorylation site mutations.
- This pathway disruption contributes to tumor progression and therapy resistance.
Related Concept Videos
02:36DNA 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...
02:36DNA 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...
02:38The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
02:37Restarting Stalled Replication Forks
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, a...
01:24Small GTPases - Ras and Rho
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
01:23Negative Regulator Molecules
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.