I. INFORMACIÓN GENERAL
4. Información de contacto
transcriptional output
Traditionally, promoter occupancy of transcription factors has been linked to gene expression level. However, a recent report studying the transcription factor Rap1 in budding yeast found that transcriptional output is correlated with a dynamic promoter turnover rate instead of the average occupancy of Rap1 at any given time
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(Lickwar et al., 2012). The study demonstrated that a higher turnover rate leads to a lower transcriptional output. Therefore, the kinetics of the Rap1 transcription factor could serve as a mechanism of regulating transcription. Activation of genes is achieved by reducing protein dynamics and increasing DNA-binding stability, probably because an increase in promoter residence time extends the time of recruiting other components of the transcription machinery. This study highlights an important role for transcription factor dynamics. In my study, recycled SUMOylation and deSUMOylation is a likely mechanism for modulating TBP dynamics. This newly uncovered function of SUMO could be more widespread. Due to the general role of SUMO in transcription, it would be interesting to know whether there are other transcription factors whose promoter kinetics are also controlled by SUMO.
In line with the notion that promoter kinetics of transcription factors is highly correlated with gene expression, another report comparing TBP turnover rates at promoters across the yeast genome obtained similar results (van Werven et al., 2009). In the study, the turnover rates of TBP at Pol I-regulated promoters, which are highly transcribed regions with continuous expression of rDNA gene, are generally the lowest. The highest turnover rate was detected at Pol II-mediated genes. This category of genes include most inducible promoters whose activation is relatively infrequent.
9.6. Potential explanation for TBP SUMO mutants effect in sporulation
A study linking TBP expression during the development of mammalian male germ cell has been undertaken. In rat and mouse cells, both TBP mRNA and protein levels are drastically overexpressed in testis compared to somatic cells during late spermatogenesis (Persengiev et al., 1996; Schmidt and Schibler, 1995). This reveals a need for TBP in this cellular stage. This might explain the sporulation defects in TBP SUMO mutants, where TBP protein stability is altered.- 142 -
Alternatively, the defect could be explained by lack of flexibility during transcription reprogramming. Transcription plasticity includes a tightly temporal control of gene expression, which is largely decided by the efficiency of recruitment and promoter clearance of TBP. In my ChIP assays looking at the activation and shut-off of the inducible heat shock gene Hsp30, the release efficiency of TBP 6KR or TBP K47R was not different from WT, both were completely cleared off from promoters 5min after switching off the promoter. However, the recruitment efficiency of TBP 6KR was impaired, and TBP K47R also showed a minor effect. This implies that transcription plasticity, in particular the recruitment of TBP, might be affected by disrupting SUMOylation of TBP, which influences the transcription reprogramming during sporulation.
On the other hand, the sporulation defects could possibly come from abnormal transcriptional output of certain TBP-transcribed genes regulated for meiosis or sporulation due to a decrease in TBP kinetics. Apart from sporulation, the defect of TBP SUMO mutants might also be observed when precise expression levels of some TBP-transcribed genes need to be strictly controlled.
9.7. Relationship between SUMOylation of Mot1 and TBP dynamics
Mot1, which has been identified as a SUMO substrate (Wang and Prelich, 2009), is a key TBP regulator which dissociates TBP from DNA in an ATP-dependent manner. It has both positive and negative roles in transcriptional regulation, and its ATPase activity is required for both activation and repression of Mot1-responsive genes (Dasgupta et al., 2002). Intriguingly, SUMOylation of mot1 mutant defective in binding to TBP is undetectable, and the mutant without ATPase activity, which is required for dissociating TBP from DNA, is highly SUMOylated (Wang and Prelich, 2009). This suggests that binding or interacting with TBP is a prerequisite for Mot1- 143 -
SUMOylation, and deSUMOylation of Mot1 occurs only when TBP is able to be released from DNA. In other words, recycled SUMOylation of Mot1 is closely related to the dynamic interaction between the two proteins. Given the function of Mot1 in destabilising TBP-DNA, as well as the effect of TBP SUMOylation in its promoter dynamics, it is interesting to speculate that SUMOylation of Mot1 takes part in the regulatory mechanism for TBP dynamics.
9.8. A proposed model for a regulatory mechanism of SUMO in
transcription
A novel role of SUMO in transcription is uncovered in my study, where SUMO controls the dynamics of TBP on promoters to regulate transcription. Figure 9-2 proposes a model describing the functional significance of SUMOylation of TBP and the consequences of blocking its SUMOylation.
In this model, DNA-bound TBP is not SUMOylated, whereas the exposure of the SUMO sites in the N-terminal domain increases the chance of SUMOylation. Once modified by SUMO, alteration of TBP configuration renders it unstable on DNA and thus it is released. TBP can rebind to promoters as soon as SUMO comes off. Recycling SUMOylation of TBP maintains normal promoter dynamics and thereby normal transcriptional output. DNA-bound TBP is prevented from degradation due to accumulation of de-ubiquitylating enzyme Ubp3 at promoters. However, since binding of TBP remains dynamic, every TBP molecule has an equivalent chance to stay in an unbound state and be degraded. By contrast, TBP 6KR is not SUMOylated, rendering DNA-bound TBP 6KR less mobile, and the generally lower promoter dynamics leads to higher transcriptional output. Moreover, lack of mobility represents
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lack of exchange between the bound and unbound group, indicating the fact that the DNA-bound TBP is less likely to be degraded and has a longer protein half-life.
Figure 9-2. The functional significance of TBP SUMOylation. The recycled SUMOylation (green
oval) of TBP WT keeps the balance between two types of TBP which are able or unable to bind to DNA. This maintains normal promoter turnover of TBP WT and thereby a normal transcriptional output (bent arrow). The ubiquitylation (orange square) and degradation of the promoter-bound TBP is prevented by de-ubiquitylating enzyme Ubp3. Free TBP molecules are accessible to proteasome degradation and are degraded. Since TBP WT keeps itself dynamic on the promoters, the DNA-bound and unbound population are constantly exchanging. On the other hand, TBP 6KR, which is not SUMOylated, binds to DNA, but it cannot switch to a close configuration (due to lack of SUMOylation) and releases from the promoter. As a consequence, the binding is much more stable. The low promoter dynamics of TBP 6KR contributes to much higher expression level. Moreover, lack of exchange between the bound and unbound group makes the DNA-bound TBP 6KR proteins less likely to be degraded and therefore longer-lived.
To provide more evidence for proposed model, future work should focus on examining whether gene expression levels are altered in TBP SUMO mutants.
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In this study, I demonstrate that SUMOylation of TBP is crucial for maintaining its promoter dynamics. Given the central role of TBP in transcription and its highly conserved characteristic, this provides insight into a novel mechanism for transcription regulation which could be conserved among species.
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