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Merotelic attachments and non-homologous end joining are the basis of chromosomal instability
Astrid Alonso Guerrero1, Carlos Martínez-A, Karel Hm van Wely
1Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, UAM Campus Cantoblanco, 28049 Madrid, Spain. kvanwely@cnb.csic.es.
Abstract:
Although the large majority of solid tumors show a combination of mitotic spindle defects and chromosomal instability, little is known about the mechanisms that govern the initial steps in tumorigenesis. The recent report of spindle-induced DNA damage provides evidence for a single mechanism responsible for the most prominent genetic defects in chromosomal instability. Spindle-induced DNA damage is brought about by uncorrected merotelic attachments, which cause kinetochore distortion, chromosome breakage at the centromere, and possible activation of DNA damage repair pathways. Although merotelic attachments are common early in mitosis, some escape detection by the kinetochore pathway. As a consequence, a proportion of merotelic attachments gives rise to chromosome breakage in normal cells and in carcinomas. An intrinsic chromosome segregation defect might thus form the basis of tumor initiation. We propose a hypothesis in which merotelic attachments and chromosome breakage establish a feedback loop that results in relaxation of the spindle checkpoint and suppression of anti-proliferative pathways, thereby promoting carcinogenesis.
Insights
Merotelic attachments cause spindle-induced DNA damage, leading to chromosome breakage and potentially initiating tumors. This defect may create a feedback loop promoting cancer by relaxing cell cycle checkpoints.
Area of Science:
- Cell Biology
- Genetics
- Cancer Research
Background:
- Most solid tumors exhibit mitotic spindle defects and chromosomal instability.
- The mechanisms initiating tumorigenesis remain largely unknown.
Discussion:
- Uncorrected merotelic attachments lead to spindle-induced DNA damage, including kinetochore distortion and centromere breakage.
- These attachments can bypass detection by the kinetochore pathway, causing chromosome breakage in both normal and cancerous cells.
- This suggests an intrinsic chromosome segregation defect as a basis for tumor initiation.
Key Insights:
- Merotelic attachments are a key driver of chromosomal instability and DNA damage in early tumorigenesis.
- A proposed feedback loop involving merotelic attachments and chromosome breakage can lead to spindle checkpoint relaxation and suppressed anti-proliferative pathways.
- This mechanism provides a unified explanation for prominent genetic defects observed in chromosomal instability.
Outlook:
- Further research into merotelic attachments could reveal novel therapeutic targets for cancer prevention and treatment.
- Understanding this mechanism may elucidate the initial steps in carcinogenesis, paving the way for early diagnostic strategies.
- Investigating the interplay between spindle defects, DNA damage, and checkpoint pathways is crucial for comprehending tumor initiation.
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