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Published on: September 20, 2019
Centriole separation in DNA damage-induced centrosome amplification.
Chiara Saladino1, Emer Bourke, Pauline C Conroy
1Centre for Chromosome Biology, Department of Biochemistry and NCBES, National University of Ireland-Galway, University Road, Galway, Ireland.
Environmental and Molecular Mutagenesis
|March 11, 2009
Summary
DNA damage triggers centrosome amplification, a process linked to cancer development. This study reveals centriole splitting as a key mechanism driving centrosome amplification following DNA damage.
Area of Science:
- Cell Biology
- Cancer Research
- Genetics
Background:
- Altered centrosome numbers are observed in tumor cells and are implicated in cancer development.
- The precise mechanism linking DNA damage to disrupted cell cycle control and centrosome duplication remains unclear.
Purpose of the Study:
- To investigate the mechanism of centrosome amplification following DNA damage.
- To determine if specific DNA repair pathways are required for centrosome amplification.
- To elucidate the role of centriole splitting in this process.
Main Methods:
- Utilizing chicken DT40 cells deficient in DNA repair proteins (DNA-PK, Ku70, H2AX, Xpa, Scc1).
- Employing ionizing radiation (IR) and topoisomerase II inhibition.
- Analyzing immortalized hTERT-RPE1 cells, U2OS osteosarcoma cells, and BRCA1/BRCA2 mutant cancer cells.
Main Results:
- Centrosome amplification occurs after IR in chicken cells lacking key DNA repair activities.
- Inhibition of topoisomerase II induces Chk1-dependent centrosome amplification.
- IR induces centriole splitting and subsequent centrosome amplification in various human cell lines, including tumor cells.
- BRCA1/BRCA2 mutations lead to increased centriole splitting, even without DNA damage induction.
Conclusions:
- Centrosome amplification is a general response to DNA damage across different cell types.
- Centriole splitting is identified as a critical step in DNA damage-induced centrosome amplification.
- These findings provide insights into the link between DNA damage, centrosome abnormalities, and cancer progression.
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The primary microtubule organizing center (MTOC) in animal cells is the centrosome. A centrosome has two cylindrical centrioles at its core. Each centriole consists of nine sets of three microtubules held together by proteins. The centrioles are positioned at right angles to each other and surrounded by a shapeless protein cloud called the pericentriolar matrix, or pericentriolar material (PCM).
To ensure that each daughter cell receives a centrosome after cell division, centrosome duplication...
To ensure that each daughter cell receives a centrosome after cell division, centrosome duplication...
02:25Centrosome Duplication
The primary microtubule organizing center (MTOC) in animal cells is the centrosome. A centrosome has two cylindrical centrioles at its core. Each centriole consists of nine sets of three microtubules held together by proteins. The centrioles are positioned at right angles to each other and surrounded by a shapeless protein cloud called the pericentriolar matrix, or pericentriolar material (PCM).
To ensure that each daughter cell receives a centrosome after cell division, centrosome duplication...
To ensure that each daughter cell receives a centrosome after cell division, centrosome duplication...
01:13Centrioles and Centrosomes
Most animal cells comprise a pair of centrioles together called a centrosome. The cell duplicates its centrosome and contains two centrosomes side-by-side, which begin to move apart during the prophase. As the centrosomes migrate to two different sides of the cell, microtubules start extending from each centrosome toward the other end. The mitotic spindle is composed of the centrosomes and their emerging microtubules.
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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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