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#11146 is telomere shortening a process or a phenotype?
There are 2 GO terms
telomere maintenance via telomere shortening
and
age-dependent telomere shortening
Are these really processes? They sound like pathological phenotypes.
There are only 8 manual annotations and I am filtering the pombe one now (it is clearly incorrect).
Telomeres do get shorter with age but isn't this because the lengthening is failing ? ...in fact some of the gene products annotated to the term are reverse trancriptases and things involved in telomere maintenance (lengthening)....how would these shorten telomeres?
Val
Telomeres only get regenerated in cells where telomerase is expressed, otherwise they do get shorter with every replication. And telomerase only gets expressed in certain cell types like germ cells.
But you're right, telomeres also shorten for other reasons like oxidative stress which may not be age-related.
I also don't understand why this term is 'telomere maintenance via telomere shortening' - how does shortening maintain telomeres if they're naturally getting shorter every replication?
And then 'age-dependent telomere shortening' is a subclass of 'telomere maintenance via telomere shortening' and that definitely isn't a type of telomere maintenance.
Maybe it's just I don't understand this...I'll ask David H and Ruth to comment...
Hi Both
just had a look at the BHF annotation to age-dependent telomere shortening. This is a NAS although probably should have been a TAS based on the statement in PMID:17395247: Thus, it can be expected that expression of telomere-binding proteins might interfere with the efficacy of telomeric SSB repair. Stabilization of the telomere higher order structure might easily lead to a decreased accessibility of telomeric DNA to DNA repair complexes. .... over-expression of TRF2 has been shown not only to stabilize the telomeric loop and to postpone uncapping, but also to accelerate telomere shortening (Karlseder et al., 2002). We therefore examined the effect of TRF2 expression on telomeric SSB repair and found that the acceleration of telomere loss by TRF2 can be explained by the inhibitory effect of this protein on telomeric SSB repair.
Then in the review: PMID:24374808 is the statement: The shelterin can affect the telomere length by blocking the action of telomerase. When the telomere is too long, more shelterin proteins are attached to the TTAGGG repeat arrays to inhibit accessibility of the telomerase. Therefore I think that telomere shortening is an active part of telomere maintainance. I don't know enough about this to know whether there will be proteins that will be annotated to telomere shortening and not lengthening, or Vice versa, which would suggest telomere maintenance is all that is required.
Nancy is back from Maternity leave next week and I was planning to put her on GO annotation and to annotate telomere processes as there is a new person (Jess Buxton) in the CVG group who is interested in telomere length and Nancy worked on telomere binding drugs previously. So can we put this on hold for a month or so and see what they think of this?
Thanks
Ruth
I don't think this is active. This is the phenotype you see when
telomerase is mutated. I don't think there is a biological process to
actively shorten telomeres.
No hurry for me though.
Val
On 11/09/2014 14:56, Ruth wrote:
Related
Ontology requests:
#11146Hi Val,
I think that's right, see also http://en.wikipedia.org/wiki/Telomere "During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened[1].
When there is no telomerase reverse transcriptase (or its activity is inhibited), chromosomes become shorter.
So, all processes containing telomere shortening should be obsoleted. The annotations may be evidence for telomere maintenance.
Cheers,
Pascale
Let's leave this until Ruth's curators are back.
I would say phenotype. It's a consequence of the end replication problem; a limit on what DNA synthesis can do. By analogy, mismatches occur due to fidelity limits for DNA polymerase, and we see more in the absence of mismatch repair. We have terms for error-prone translesion synthesis (GO:0042276), but we wouldn't have a process term for misincorporation to form DNA mismatches (I think).
Hi All
thank you for giving me and Nancy some time to think about this.
We agree these are phenotypes and the terms should be obsoleted. So that information is not lost when these GO terms are obsoleted please could the following terms be created:
NEW GO term negative regulation of telomeric single strand break repair
with 2 is_a parents:
GO:0032205 negative regulation of telomere maintenance
New GO term (term genie) GO:1903517 Label: negative regulation of single strand break repair which is a neg reg child of GO:0000012 single strand break repair
In PMID:17395247 the authors state: Repair of single strand breaks in telomeric DNA is less efficient than in other genomic regions, therefore we feel that it is important to have a location specific term here. Based on the definition of 'GO:0032205 negative regulation of telomere maintenance' it seems that single-stranded DNA repair of telomeres will be a type of telomere maintenance.
Thanks
Ruth
Hi Ruth,
But is "telomeric single strand break repair" a different process to other single strand break repair? I thought that it being a different process was a criteria for a new process term. It could just be less efficient due to accessibility or other reasons, rather than real "regulation" of "telomeric single strand break repair", especially in an overexpression assay. Again this sounds like a phenotype to me.....
val
Hi Val
yes I can see where you are coming from. I do however think this is more than just a 'phenotype'.
I guess we just wanted to be able to capture that there are proteins which need to protect the telomere from single strand break repair as the telomere needs to have it's single strand DNA end and if this is not protected it would be repaired and then it would cause problems when the DNA is replicated, and lead to chromosomal end to end fusions. Much of this is covered by the GO term GO:0016233 telomere capping. Definition: A process in which telomeres are protected from degradation and fusion, thereby ensuring chromosome stability by protecting the ends from both degradation and from being recognized as damaged DNA. May be mediated by specific single- or double-stranded telomeric DNA binding proteins.
However, we were asking for a more specific statement. ie to capture just part of the telomere capping definition 'protecting the ends from being recognized as damaged DNA'.
We could just annotate this as GO:1903517: negative regulation of single strand break repair and then have C16 information occurs_in Telomere. The telomere obviously has a very different protein/DNA structure compare to the rest of the chromosome.
There is GO:0043504 mitochondrial DNA repair, which presumably occurs by the same mechanism as nuclear DNA repair. Although perhaps there are different proteins involved in this process.
Ruth
I can ask my local telomere expert to weigh in if you like. Is it really single-strand break repair or double-strand break repair where there is ss overhang?
You are probably right, if you think its real regulation, but its the same genes (i.e process) we would add occurs_at telomere.
My take is that the mitochondrial repair is different, even if the mechanism is the same because its different sets of gene product involved.
I didn't think it was regulation, because the telomere capping complex is always present in the WT/normal cell isn't it? the processes are dissected by mutating or overexpressing the cap binding complex and seeing that the single stranded DNA is repaired by gap filling or whatever. Isn't this just preventing the single strand region from being repaired in a normal cell, rather than regulating a process which normally occurs.
I guess my thinking is that if something provides an barrier to a process ever occurring is that regulation? If a mechanism existed to relieve the inhibition then I would say it was negative regulation.
(maybe my concept of regulation is a bit skewed)
Another key question is whether the recombination community would expect to see the telomere binding proteins annotated to recombination via regulation?
Now I'm not sure.....
Hi Jim,
That would be useful.
The question is, is it "negative regulation of recombination"
Val
Hi,
Mulling this over, I think I am probably over thinking it. It does seem that it is negative regulation as defined by GO, if the purpose of the cap is to suppress recombination. I would go ahead Ruth.
Val
So the summary for this ticket is:
obsolete
Process GO:0001309 age-dependent telomere shortening
Process GO:0010834 telomere maintenance via telomere shortening
Add
NEW GO term negative regulation of telomeric single strand break repair
with 2 is_a parents:
GO:0032205 negative regulation of telomere maintenance
GO:1903517 Label: negative regulation of single strand break repair which is a neg reg child of GO:0000012 single strand break repair
Obsoletion notice sent out 20 Jan.
Added:
ID: GO:1903823 Label: telomere single strand break repair
Added:
ID: GO:1903824 Label: negative regulation of telomere single strand break repair
Note: these terms just need obsoleting to be replaced with (consider) the new terms after 3 Feb.
Done: obsoleted:
GO:0001309 age-dependent telomere shortening
GO:0010834 telomere maintenance via telomere shortening