1. Pathways to genetic instability
Pathways to genetic instability. Different types of genetic instability require a different number of mutational “hits” in order to engender the respective instability phenotype. In a heterozygote with one defective nucleotide excision repair (NER) allele (step 1), inactivation of the normal allele (step 2) does not immediately lead to mutations. It additionally requires exposure to an environmental agent (i.e., ultraviolet light) (step 3) to create large numbers of mutations (NER-related instability; NIN). In contrast, in a heterozygote with one defective mismatch repair (MMR) allele (step 1), all that is required to begin to develop mutations at a high rate (microsatellite instability; MIN) is the inactivation of the normal allele inherited from the unaffected parent (step 2). Cell fusion and other experiments suggest that chromosomal instability (CIN) can have a dominant quality.29 One example of a gene that can be mutated in a dominant negative manner to cause CIN is hBub1, a component of the mitotic spindle checkpoint (MSC).30 It apparently requires only a single mutational “hit” of such a gene to engender the CIN phenotype.
Source: Tumor Genome Instability, The Online Metabolic and Molecular Bases of Inherited Disease
Citation: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. The Online Metabolic and Molecular Bases of Inherited Disease; 2014 Available at: Accessed: October 09, 2017
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