User:Jvand258/sandbox

Article draft for derepression

In genetics, repression is a mechanism often used to decrease or inhibit the expression of a gene. Removal of repression is called derepression. This mechanism may occur at different stages in the central dogma, with the result of increasing the overall RNA or protein products in the cell. Dysregulation of derepression can result in altered gene expression patterns and negative phenotypic consequences, such as disease. 

Derepression of transcription

Transcription can be repressed in a variety of ways, and therefore can be derepressed in different ways as well. A common mechanism is a substrate causing a conformational change in a repressor protein bound upstream of a gene, such as in an operator sequence. This allosteric regulation would take away the repressor’s ability to bind DNA, thus removing the repressive effect on transcription [CITE].

Another form of transcriptional derepression uses chromatin remodeling complexes. For transcription to occur, RNA polymerase needs to have access to the promoter sequence of the gene. Sometimes these sequences are wrapped around nucleosomes or are in condensed heterochromatin regions, and are therefore inaccessible. Through the mechanism of chromatin remodeling these promoter sequences can become accessible to the RNA polymerase, and transcription becomes derepressed [CITE].

Transcriptional derepression may also occur at the level of transcription factor activation. Certain families of transcription factors are non-functional on their own because their catalytic domains are blocked by another part of the protein [CITE]. Substrate binding to this second, regulatory domain causes a conformational change which allows access to the catalytic domain [CITE]. This allows the transcription factor to bind the DNA and serve its function, thus derepressing the gene. 

Derepression of translation

Derepression of translation increases protein production without altering the levels of mRNA in the cell. miRNAs are a common mechanism of translation repression, binding to the mRNA through complimentary base pairing to silence them [CITE]. Certain RNA binding proteins have been shown to target untranslated regions of the mRNAs and upregulate the translation initiation rates by alleviating the repressive miRNA effects [CITE]. 

Examples of derepression

Auxin signalling

Another example is the auxin mediated derepression of the auxin response factor family of transcription factors in plants. These auxin response factors are repressed by Aux/IAA repressors. In the presence of auxin, these Aux/AII proteins undergo ubiquitination and are then degraded [CITEx2]. This derepresses the auxin response factors so they may carry out their functions in the cell. 

Altered derepression causing diseases

Familial Alzheimer’s disease

Alzheimer’s is a neurodegenerative disease involving progressive memory loss and other declines in function. One common cause of familial Alzheimer’s is mutations in the PSEN1 gene.[CITE] This gene encodes a protein that cleaves intracellular peptides, which promotes CBP degradation in the cytoplasm. Mutations in PSEN1 decrease the amount of cleavage occurring, thus derepressing CBP’s ability to upregulate transcription of certain other genes. [CITE]

Rhett syndrome

Rhett syndrome is a neurodevelopmental disorder involving deterioration of learned language and motor skills, autism, and seizures. Many cases of Rhett syndrome are associated with mutations in MECP2, a gene encoding a transcriptional repressor.[CITE] Mutations in this gene decrease the levels of MeCP2 binding to different promoter sequences, derepressing them. The increased expression of these MeCP2 regulated genes in neurons contribute to the Rhett syndrome phenotype. [CITEx2]

Beckwith-Wiedemann syndrome

This syndrome is associated with an increased susceptibility of tumors and growth abnormalities in children. A common mutation causing this syndrome is in an imprint control region near the Igf2 gene.[CITE] This imprint control region is normally bound by an insulator which represses an enhancer from acting on the Igf2 gene on the maternal allele, but is absent and allows access on the paternal allele. Mutations in this imprint control gene inhibit the insulator from binding, which derepresses enhancer activity on the maternal allele. This abnormal derepression and increase in gene expression is a cause of Beckwith-Wiedemann syndrome. [CITE]

Proposed changes for derepression

Changes

• Adding a section on how alterations in derepression can result in diseases, with one or two examples
• Talk about transcriptional and translational derepression
• Give one or two examples of derepression in natural biological systems (they have a section currently on a drug causing derepression)
• Add one or two images showing derepression, and possibly one of the examples

Sources .

Topic choices

Derepression (the topic I am assigned to)

• Could give examples, such as in many plants or in some DNA repair mechanisms
• Could add more to the introduction paragraph as it is currently 2-3 sentences
• Could give a better explanation of what derepression is (how some genes are have everything ready to go, but are just waiting for their repressor to leave)
• Could add an image or two showing derepression
• Could talk about why derepression would be important (especially for genes that need to activated quickly)
• Definitely add more references (that I would use) because there is currently one plus a link to a website

Germline mutation

• Could add about how they come to be, specifically with respect to the timing of the mutation affecting whether it becomes germline, somatic, or both
• Could also talk about a few more ways that these mutations can occur (they only have oxidative damage)
• Could add an image or two to show the difference between germline, somatic, and a mix of the two in the body (affected areas)
• Could change the formatting a bit (shorter introduction, then an overview section)to make the page easier to follow, and move some of the information (there is a sentence or two in the "Oxidative DNA damage and mutation" section that belongs in the introduction or an overview section instead).

TATA box

• Could remove a link to a page that no longer exists

Deoxyribonucleotide

• Could add images and more examples

Article evaluation

Nick (DNA)

• Many cases where there was no citation until the end of a long paragraph when there were several statements within it that seemed like they should have been cited on their own.
• The introductory paragraph is pretty short, and should include each of the three major functions of nicks explained in the article (it only mentions two).
• I appreciated the flow from the formation of nicks to their repair, and then finishing off with their biological implications.
• Their three step process for ligation of nicks doesn't match up with what the picture included shows, causing a conflict of information.
• The "Formation of nicks" section talks about how they unwind coiled DNA, but how they do this isn't explained until the very last paragraph of the article. This information should be together instead of wondering the whole article about how it works and then finally finding out at the end.
• There are a ton of tun on sentences with several commas that should have been replaced with periods.
• Once or twice, such as in the first paragraph of the "Biological implications" section, the article included examples that seemed to over complicate and draw away from the point. They also brought in new terms/names that seemed to come out of nowhere and weren't well introduced or explained sometimes.
• The third paragraph in under the "Role in replication and transcription" subheading introduces us to three new applications of nicks, but then doesn't explain or go into any detail about them. These would be great points to expand on in further improvements.
• One of the sources does not have a link. Not sure if it isn't online, or if no one has added a link to it yet.
• The sources seem quite reputable.
• None of the sources are from later than 2015. information from newer studies should be incorporated.
• There is a bias in this article towards DNA nicks being beneficial. It briefly mentions once or twice that different things can cause nicks, but it never talks about any negative implications of them.
• Most of the talk page is Peer Reviews, and there is a summary of changes someone made.
• This article is ranked as a C and high importance. It is or was also the subject of a Wiki Education Foundation-supported course assignment.