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S phase damage sensing checkpoints in mammalian cells
J M Larner1, H Lee, J L Hamlin
1Department of Radiation Oncology, University of Virginia School of Medicine, Charlottesville 22908, USA.
Abstract:
Mammalian cells have evolved multiple responses for dealing with DNA damage. One response is to acutely downregulate DNA synthesis at the initiation step. Essentially nothing is known about the initial signal that activates this SDS pathway or the macromolecules involved in transducing the signal into the final inhibitory step at origins. Determining whether any radiation induced changes in known proteins involved in cell cycle regulation or in other signal transduction pathways are primary or secondary responses to DNA damage constitutes a major challenge to identifying members of the pathway. It may turn out to be easier to identify the final mediator in the pathway, namely the protein(s) whose interaction with origins is ultimately affected by radiation. Hopefully, mutations in SDS genes in genetically tractable systems such as S cerevisiae or Schizosaccharomyces pombe will allow the identification of homologous genes in mammals. Most tumour cells are TP53 negative, and yet it is not clear that TP53 status influences radiation sensitivity. The SDS pathway may therefore represent an important protective mechanism that stands in the way of effective tumour cell killing by radiation therapy. It is hoped that an understanding of this pathway will provide opportunities for developing novel antineoplastic targets and/or radiation sensitizers.
Insights
Mammalian cells downregulate DNA synthesis upon DNA damage via the SDS pathway. Understanding this pathway could improve cancer therapy by targeting tumor cells more effectively.
Area of Science:
- Cellular biology
- Molecular biology
- Genetics
Background:
- Mammalian cells possess multiple DNA damage response mechanisms.
- One critical response involves the acute downregulation of DNA synthesis initiation, known as the DNA synthesis suppression (SDS) pathway.
- The initial signaling events and molecular players activating the SDS pathway remain largely unknown.
Purpose of the Study:
- To elucidate the initial signals and macromolecules involved in the DNA synthesis suppression (SDS) pathway.
- To identify the final mediator proteins that regulate origin interactions in response to DNA damage.
- To explore the potential of the SDS pathway as a therapeutic target in cancer treatment.
Main Methods:
- Investigating radiation-induced changes in cell cycle regulators and signal transduction proteins.
- Identifying proteins whose interaction with DNA replication origins is altered by radiation.
- Utilizing genetic studies in model organisms like S. cerevisiae and S. pombe to identify homologous mammalian genes.
Main Results:
- Challenges exist in distinguishing primary DNA damage responses from secondary effects on known regulatory proteins.
- Identifying the terminal mediator(s) of the SDS pathway may be a more feasible approach.
- Homologous SDS genes in mammals could potentially be identified through studies in yeast.
Conclusions:
- The SDS pathway represents a significant protective mechanism in mammalian cells against DNA damage.
- This pathway's role in protecting normal cells may hinder effective tumor cell killing by radiation therapy.
- Understanding the SDS pathway offers potential for developing novel anticancer therapies and radiation sensitizers.