Cells have several mechanisms to prevent the production and accumulation of trun

Question

Cells have several mechanisms to prevent the production and accumulation of truncated protein fragments. To illustrate why these fragments can be deleterious, consider a transcriptional activator protein called Groovy that binds to an enhancer element upstream of the Zippy gene. The Groovy has 2 domains, a DNA-binding domain at its N-terminus that binds to DNA at the Zippy gene and a domain that binds a histone-modifying enzyme at its C-terminus. When the second domain binds a histone-modifying enzyme, the histone modifying enzyme alters the chromatin structure at the Zippy gene leading to increased transcription of Zippy.

A. If a cell makes substantial amounts of an N-terminal fragment of Groovy, containing the DNA-binding domain alone, what is likely to happen to transcription of the Zippy gene (increase, decrease or stay the same)?

B. If, in addition to the N-terminal fragment of Groovy, a cell also makes an equal amount of the full-length protein, what is likely to happen to transcription of the Zippy gene (increase, decrease or stay the same)?

C. Consider two cell lines or strains that each have a fully functional allele of the Groovy gene on one copy of chromosome 3. On the second copy of chromosome 3, strain 1 lacks a second Groovy allele whereas strain 2 contains the Groovy allele that codes for the N-terminal fragment described in part A. If strain 1 and strain 2 have different amounts of Zippy mRNA, which do you expect to have more Zippy mRNA? Explain.

Explanation / Answer

The accumulation of insoluble polyQ-containing protein aggregates in intranuclear and perinuclear inclusions has also been detected in brains of HD transgenic mice (Davies et al., 1997) and HD patients (DiFiglia et al., 1997). These findings have led to the hypothesis that HD as well as the related glutamine repeat disorders spinal bulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and the spinocerebellar ataxia types 1, 2, 3, 6, and 7 (for review, see Paulson, 1999) are caused by the accumulation of insoluble protein aggregates in neuronal inclusions; however, to this day it is still unclear whether the formation of inclusion bodies causes dysfunction and neurodegeneration, or whether it is merely a defense mechanism to protect neuronal cells from the toxicity of misfolded proteins. In support of the second possibility, Saudouet al. (1998) and Klement et al. (1998) presented evidence that the formation of inclusion bodies with aggregated polyQ-containing protein is nontoxic or even beneficial for neuronal cells. In strong contrast to these findings, other investigators have demonstrated that formation of protein aggregates correlates with disease progression and the development of neuronal symptoms (Davieset al., 1997; Ona et al., 1999; Yamamoto et al., 2000). Very recently, using a conditional mouse model of HD,Yamamoto et al. (2000) showed that expression of mutant HD exon 1 protein results in inclusion body formation and progressive motor dysfunction. Blockage of HD exon 1 expression in symptomatic mice led to disappearance of the inclusions and the behavioral phenotype. Thus, inclusion body formation and disease progression appear to be clearly linked. Furthermore, the development of an HD-like pathology is dependent on the continuous expression of a truncated huntingtin protein with a polyQ repeat in the pathological range.

Immunohistochemical and ultrastructural studies have shown that the aggregated huntingtin protein in neuronal inclusions of HD transgenic mice and patients is ubiquitinated (Davies et al., 1997;DiFiglia et al., 1997). These findings suggest that the mutant huntingtin protein has been marked for degradation by the ubiquitination machinery but that it is apparently resistant to degradation. Degradation of most proteins by the proteasome requires the conjugation of multiple ubiquitin molecules (Bonifacino and Weissman, 1998). Ubiquitinated proteins are then recognized and hydrolyzed by the 26S proteasome (Voges et al., 1999). The 26S proteasome is composed of two major subcomplexes: the 20S proteasome, a barrel-shaped multicatalytic protease, and the 19S (PA700) regulatory complex, which associates with the 20S proteasome. The 19S regulatory complex is required for the recognition of ubiquitinated proteins. In addition to the 19S complex, a second regulator of the 20S proteasome has been described. This ring-shaped structure was termed 11S or PA28 and binds to the 20S proteasome in an orientation similar to that of 19S. The 11S subcomplex is mainly required for the degradation of short peptides rather than large ubiquitinated proteins.
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