genomic instability
Genomic instability can be divided into 2 categories: chromosomal instability (CIN) and microsatellite instability (MSI).
CIN has been linked to aneuploidy and chromosomal aberrations, and high-level loss of heterozygosity (LOH-H) has been suggested to be an indicator of CIN.
High-level MSI (MSI-H), which results from nonfunctional mismatch repair, has previously been suggested to be mutually exclusive with CIN.
For example, the most common form of genomic instability observed in colorectal cancer is chromosomal instability (CIN), whose molecular bases remain to be determined.
RECQLs and genomic instability
The three genetic disorders associated with RECQLs mutations (Bloom syndrome, Werner syndrome, Rothmund-Thomson syndrome) are associated with a inherent genomic instability.
In the case of Bloom syndrome cells, this instability is manifested as a 10-fold elevated frequency of homologous recombination events, including reciprocal exchanges between sister-chromatids and homologous chromosomes. Werner syndrome cells do not show elevated SCE frequencies, but they do display increased illegitimate recombination and a high frequency of large chromosomal deletions.
The genomic instability of RTS cells has not been analysed in detail, but there are reports of an increased frequency of chromosome aberrations.
p53 and genomic stability
Mutations in TP53, encoding p53, which has been dubbed the ‘guardian of the genome’, are seen in >50% of all sporadic cancers in humans. p53 functions in a highly dynamic and controlled manner; induction of p53 leads to cell cycle arrest in G1 and/or G2, allowing time for DNA repair to take place, but may additionally lead to apoptotic cell death. Moreover, the loss of p53 results in genomic instability.
Genomic instability diseases
- XPD
- XPB
- WRN
- BLM
See also
genetic instability syndromes with progeroid features
References
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