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DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis
1Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 78245, USA.
Abstract:
Several newly identified tumor suppressor genes including ATM, NBS1, BRCA1 and BRCA2 are involved in DNA double-strand break repair (DSBR) and DNA damage-induced checkpoint activation. Many of the gene products involved in checkpoint control and DSBR have been studied in great detail in yeast. In addition to evolutionarily conserved proteins such as Chk1 and Chk2, studies in mammalian cells have identified novel proteins such as p53 in executing checkpoint control. DSBR proteins including Mre11, Rad50, Rad51, Rad54, and Ku are present in yeast and in mammals. Many of the tumor suppressor gene products interact with these repair proteins as well as checkpoint regulators, thus providing a biochemical explanation for the pleiotropic phenotypes of mutant cells. This review focuses on the proteins mediating G1/S, S, and G2/M checkpoint control in mammalian cells. In addition, mammalian DSBR proteins and their activities are discussed. An intricate network among DNA damage signal transducers, cell cycle regulators and the DSBR pathways is illustrated. Mouse knockout models for genes involved in these processes have provided valuable insights into their function, establishing genomic instability as a major contributing factor in tumorigenesis.
Insights
This review details DNA repair and cell cycle checkpoints, focusing on proteins like ATM and BRCA1. Understanding these pathways reveals how genomic instability contributes to cancer development.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Tumor suppressor genes (e.g., ATM, NBS1, BRCA1, BRCA2) are crucial for DNA double-strand break repair (DSBR) and DNA damage response.
- Proteins involved in DNA repair and checkpoint control have been extensively studied in yeast and mammalian cells.
Purpose of the Study:
- To review proteins regulating G1/S, S, and G2/M cell cycle checkpoints in mammalian cells.
- To discuss mammalian DNA double-strand break repair (DSBR) proteins and their functions.
- To illustrate the complex network connecting DNA damage signaling, cell cycle regulation, and DSBR pathways.
Main Methods:
- Literature review focusing on proteins involved in DNA damage response and cell cycle control.
- Analysis of conserved and novel proteins in checkpoint activation and DSBR.
- Examination of data from mouse knockout models.
Main Results:
- Identified key proteins in DNA double-strand break repair (DSBR) and checkpoint activation, including ATM, NBS1, BRCA1, BRCA2, Mre11, Rad50, Rad51, Rad54, and Ku.
- Demonstrated interactions between tumor suppressor gene products, repair proteins, and checkpoint regulators.
- Established genomic instability as a significant factor in tumorigenesis through studies of mouse models.
Conclusions:
- The intricate network of DNA damage response, cell cycle regulation, and DSBR pathways is essential for maintaining genomic stability.
- Defects in these pathways, often involving tumor suppressor genes, lead to genomic instability and contribute to cancer.
- Understanding these molecular mechanisms provides insights into cancer development and potential therapeutic targets.