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NTR: single strand DNA repair #26500

Closed RLovering closed 9 months ago

RLovering commented 10 months ago

Please provide as much information as you can:

pgaudet commented 10 months ago

Hi @RLovering It would be great to align to DNA repair pathways -

Thanks, Pascale

RLovering commented 10 months ago

Hi Pascale

your suggestion seems very sensible. I am not sure how useful having a term for ssDNA mechanisms v just DNA mechanisms would be. Maybe this would just increase the number of terms unneccessarily. But some enzymes do seem to prefer ssDNA rather than dsDNA so maybe this is useful?

The article you found is very nice, I always try to get more recent articles in case there has been a change in the understanding. So all but one of the pathways in their Figure 1 are covered by GO terms: (1) the direct reversal pathway, (2) the mismatch repair (MMR) pathway GO:0006298, (3) the nucleotide excision repair (NER) pathway, GO:0006283 (4) the base excision repair (BER) pathway GO:0006284, (5) the homologous recombination (HR) pathway, GO:0000725 (GO has terms for ss and ds repair here) and (6) the non-homologous end joining (NHEJ) pathway GO:0006303.

Note that the term GO:0006307 DNA dealkylation involved in DNA repair does exist, so perhaps the new term you suggest (reversal of alkylating DNA damage) is not needed? the term you suggest could be added as a synonym? It just wasn't clear that this term would be kept.

Therefore, I will associate the term GO:0006307 DNA dealkylation involved in DNA repair with the ALKBH3 and FTO - if you decide to remove this term presumably the annotations can be moved to 'reversal of alkylating DNA damage' if that is a new terms. And I will make sure the other proteins are associated with the terms you suggest.

Other than DNA repair other DNA modifications need to be put into context of the processes they contribute to. We also need to link DNA methylation and demethylation with regulation of gene expression/epigenetics https://www.abcam.com/epigenetics/dna-methylation-and-demethylation : 'Active DNA demethylation occurs in a cycle, starting with 5mC and finishing with an unmodified C. 5mC is initially oxidized to 5-hydroxymethlcytosine (5hmC), which is further oxidized to 5-formylcytosine (5fC), and finally, this is oxidized once more to 5-carboxylcytosine (5caC). 5fC and 5caC can be removed from DNA by thymine DNA glycosylase (TDG) in combination with base excision repair (BER) to result in an unmodified C.'

Obviously demethylation pathway ends with BER but the repair was not to 'damaged DNA' but part of changing the epigenetics status of the DNA.

So for this there are: GO:0044027 negative regulation of gene expression via CpG island methylation GO:0044029 positive regulation of gene expression via CpG island demethylation Although only 4 genes are associated with these terms, based on expt data, and I don't think any are demethylases. So looking at Wikipedia: https://en.wikipedia.org/wiki/DNA_demethylation and then the UniProt records and PubMed the following human genes need to be associated with the GO:0044029 positive regulation of gene expression via CpG island demethylation term: TET1 Q8NFU7 - UniProt OGG1 O15527 - https://pubmed.ncbi.nlm.nih.gov/35098021/ EGR1 P18146 - https://pubmed.ncbi.nlm.nih.gov/35098021/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715719/ TET2 Q6N021 - UniProt; https://pubmed.ncbi.nlm.nih.gov/24315485/ TET3 O43151 - UniProt

Have created these GO:0044029 positive regulation of gene expression via CpG island demethylation annotations

Ruth

RLovering commented 10 months ago

PS for RNA repair is it worth having GO:0042245 RNA repair is_a child: RNA dealkylation involved in RNA repair? I haven't looked at other mechanisms of RNA repair but FTO is supposed to be involved in this process

RLovering commented 10 months ago

PPS I am leaving oxidative single-stranded DNA demethylation for now (PMID:18775698, 17991826) - waiting for you to confirm if ssDNA terms will be created. If not to be created will delete.

ValWood commented 10 months ago

I'm not sure how accurate this is but: User which pathways repair single-stranded DNA ChatGPT Several pathways are involved in repairing single-stranded DNA (ssDNA) lesions in cells. These pathways primarily function during DNA replication or in response to damage. Some of the key mechanisms include:

Base Excision Repair (BER): BER repairs small, non-helix-distorting lesions, such as damaged bases or single-strand breaks. It involves the removal of the damaged base by a DNA glycosylase enzyme, followed by endonuclease action, gap filling, and ligation.

Nucleotide Excision Repair (NER): NER primarily repairs bulky lesions caused by UV radiation or chemical carcinogens. While it typically targets double-stranded DNA lesions, it can also handle certain types of single-strand lesions, albeit indirectly by removing larger damaged stretches.

Mismatch Repair (MMR): MMR primarily corrects base-pairing errors that occur during DNA replication, preventing the accumulation of mismatched base pairs. It recognizes and repairs these mispaired bases, predominantly during the S phase of the cell cycle.

Homologous Recombination (HR): HR is involved in repairing DNA double-strand breaks (DSBs) but can also participate in repairing ssDNA lesions. It uses an undamaged homologous DNA sequence as a template to repair the damaged strand, promoting accurate repair.

Non-Homologous End Joining (NHEJ): While primarily involved in repairing DNA double-strand breaks, NHEJ can also handle certain types of single-strand breaks by directly ligating the ends of the damaged DNA strands.

Single-Strand Break Repair (SSBR): Specifically dedicated to the repair of single-strand breaks, SSBR involves the detection and sealing of nicks or gaps in the DNA backbone, preventing further damage.

This means that a general single-strand repair term might be problematic because it can't be a parent of all of these pathways. Perhaps create the Single-Strand Break Repair (SSBR) pathway if it is correct,

rather than a generic single strand repair term, but otherwise, make sure that the definitions of the other processes describe which types of lesions they can repair?

RLovering commented 10 months ago

Good point it might be difficult to decide, when curating, if the repair is ss or ds, but remember changing a modificated base is not a break repair. GO:0000012 single strand break repair already exists, probably needs the exact synonyms to be added: Single-Strand Break Repair pathway SSBR pathway

So some of the modified bases are methylated and may be demethylated -which are part of epigenetic modifications therefore not repair, others are modified due to damage. https://pubmed.ncbi.nlm.nih.gov/18775698/ and https://pubmed.ncbi.nlm.nih.gov/31981739/

pgaudet commented 10 months ago

@ValWood according to @colinlog, ChatGPT was a bit creative here, these pathways are for dsDNA, it is not clear that single-stranded DNA is repaired in cells, but it seems like people single-stranded DNA in assays, for some reason.

ValWood commented 10 months ago

OK! is singe-stranded DNA not repaired by any pathway? (that would make sense I guess). I shouldn't comment on DNA repair tickets because its over 10 years since I have annotated any!

pgaudet commented 10 months ago

According to Colin, this is not physiological.

MarijaOM commented 10 months ago

Reactome does not show SSBR as an independent pathway but as a component of base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR) pathways. In all three cases, SSBs are enzymatically created either upon removal of damaged bases (BER) or in the process of excision of damaged (NER) or mismatched (MMR) nucleotides. This is followed by gap filling by DNA polymerases and, finally, ligation of the nick by DNA ligases. The combinations of endonucleases that create SSBs and DNA polymerases that fill in the gaps differ between BER, NER, and MMR. If there is an SSB with no additional damage to surrounding bases, it is likely just simply ligated, which on its own does not constitute a pathway. The involvement of DSBR mechanisms in SSBR is true only in the sense that a DSB is nothing more than two SSBs across each other in close proximity. In essence, different SSBR mechanisms exist as subpathways of other DNA repair pathways. When SSBs occur on their own, with no additional damage, is their sealing a physiological process or just a molecular function of DNA ligases?

colinlog commented 10 months ago

I'd say the DNA polymerisation and ligation catalytic steps are MFs within each of these DNA repair processes (BER, MMS, NER).

What Pascale and I were trying to convey, is that although the cellular reactants on which the enzymes catalyse reactions are formally speaking single DNA strands, they are in fact base paired with a second antiparallel complementary DNA strand. That is what was damged in the first place and that is what the repair pathway products are. These are therefore double strand DNA repair pathways.

It is not the case that two 'loose single strands get ligated' or that 3'OH group of a n unpaired single DNA strand is used to add nucleotides, as can be seen when RNA polyadenylase or terminal transferases add adenosine to the 3'end of a single strand nucleic acid polymers.

On Tue, Dec 12, 2023 at 6:18 PM MarijaOM @.***> wrote:

Reactome does not show SSBR as an independent pathway but as a component of base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR) pathways. In all three cases, SSBs are enzymatically created either upon removal of damaged bases (BER) or in the process of excision of damaged (NER) or mismatched (MMR) nucleotides. This is followed by gap filling by DNA polymerases and, finally, ligation of the nick by DNA ligases. The combinations of endonucleases that create SSBs and DNA polymerases that fill in the gaps differ between BER, NER, and MMR. If there is an SSB with no additional damage to surrounding bases, it is likely just simply ligated, which on its own does not constitute a pathway. The involvement of DSBR mechanisms in SSBR is true only in the sense that a DSB is nothing more than two SSBs across each other in close proximity. In essence, different SSBR mechanisms exist as subpathways of other DNA repair pathways. When SSBs occur on their own, with no additional damage, is their sealing a physiological process or just a molecular function of DNA ligases?

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pgaudet commented 10 months ago

Thanks for the comments - my understanding is that we have all the terms that we need. Closing this one,