DNA polymerases: obsolete

[gocentral]

This may have come up before. The DNA polymerae activity tree has a "few" terms (like maybe all) that need to removed, as they are really gene products: DNA-directed DNA polymerase activity alpha DNA polymerase activity beta DNA polymerase activity delta DNA polymerase activity DNA polymerase processivity factor activity *** DNA polymerase V activity epsilon DNA polymerase activity eta DNA polymerase activity gamma DNA-directed DNA polymerase activity iota DNA polymerase activity kappa DNA polymerase activity lambda DNA polymerase activity mu DNA polymerase activity nu DNA polymerase activity sigma DNA polymerase activity theta DNA polymerase activity zeta DNA polymerase activity

Except for the one with ***, these all appear to catalyze the same reaction and appear to be distinquished in some cases by the cell type that expresses it. Others appear to be a low vs high fidelity type of thing, which really needs to be assigned some sort of "proof- reading activity" or some such thing. I think the term "DNA-directed DNA polymerase activty " just about captures it all (the template dependence, etc.)

Reported by: hdrabkin

Original Ticket: "geneontology/ontology-requests/2489":https://sourceforge.net/p/geneontology/ontology-requests/2489

[gocentral]

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Hi Harold,

There was a proposal a while back to obsolete and re-organize DNA polymerase terms based on some intrinsic functional differences - processivity, fidelity, etc.

But here are some URLs to old go mailing list conversations which have links to old SourceForge items.

http://www.geneontology.org/email-go/go-arc/go-2004/1069.html http://www.geneontology.org/email-go/go-arc/go-2004/1120.html

eurie

Original comment by: eurie

[gocentral]

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Yes, too many of these are gene products, but I don't think we need to (or should) go to the extreme of obsoleting all but the parent 'DNA-directed DNA polymerase activity'. Most of the existing DNA polymerase terms can become narrow synonyms of new terms, which will allow biologists to use the familiar names for searching.

Processivity and some aspects of substrate specificity are reasonable grounds for classifying DNA polymerases further. For substrate specificity, distinctions that depend on DNA sequence (as opposed to subcellular localization or expression pattern) would be OK.

Furthermore, now that we have agreed in principle to allow some kinds of 'complex' functions, notably coupled activities, in the function ontology, things like the intrinsic DNA glycosylase Eurie mentioned in the earlier email exchange would be legitimate distinguishing features as well.

e.g. DNA polymerase activity coupled to DNA glycosylase activity

Similarly, a proofreading polymerase activity might be thought of as coulped polymerase and nuclease activities

e.g. DNA polymerase activity coupled to exonuclease activity (exact(?) synonym proofreading DNA polymerase activity, related synonym high fidelity polymerase activity)

(Please double-check the suggested synonym types and coupled activities above ... I'm dredging this up from Very Long Ago.)

m

Original comment by: mah11

[gocentral]

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as I see from the links Eurie supplied; this IS an old problem, but it hasn't been addressed. example: " pol alpha is involved in the initiation of DNA replication and lagging strand elongation. I am loathe to create process grouping terms such as 'DNA repair polymerase activity', but at the same time it seems wrong to have terms representing the specific polymerases (even if they do incorporate more info). Can anyone suggest a solution? "

Wouldn't this be best resolved in annotating the protein product to the process of initiation of DNA preplication and the function DNA dependent DNA polymerase? Otherwise, we are using the activities to describe the processes? This doesn't seem to be a case of complex activities, but more of multiple processes using the same reaction (function)?

Original comment by: hdrabkin

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I don't think anyone is proposing (this time round) to organize the function terms for DNA polymerases based on the processes that a given gene product is involved in. Rather, although many of the existing terms should be obsolete, I think we can have some legitimate subclasses of DNA polymerase, because there are ways to organize the polymerase activities based on criteria that are really aspects of function.

m

Original comment by: mah11

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this info comes from a previous SF item, which I'm going to close, since it's so far down the pile that it's been forgotten.

Date: 2004-04-27 08:44 Sender: girlwithglasses Logged In: YES user_id=473796

Still remaining: theta - repair of interstrand crosslinks nu - low fidelity DNA-directed DNA polymerase involved in translesion DNA synthesis (ie. error-prone translesion synthesis) - want to research this more first.

--

There is a particularly lovely table at http://www.journals.royalsoc.ac.uk/ link.asp?id=h0gpp7n2d1qj6c0t which summarizes the roles of the DNA polymerases. I would suggest obsoleting all the 'x DNA polymerase activity' terms and replacing them all with the generic DNA-directed DNA pol activity term plus term(s) to describe their function.

Here are some suggested terms for some of the polymerases. References are PMID:12045093 and PMID:11253362.

DNA polymerase V activity ; GO:0008723 -->translesion synthesis - TLS ; GO:new low fidelity synthesis - DNA replication ; GO:0006260 SOS lesion-targeted and untargeted mutagenesis - mutagenesis ; GO:0006280

alpha DNA polymerase activity ; GO:0003889 -->initator pol, lagging strand pol DNA replication initiation ; GO:0006270 lagging strand elongation ; GO:0006273

beta DNA polymerase activity ; GO:0003890 --> base-excision repair ; GO:0006284 recomb pol - DNA recombination ; GO:0006310 meiosis pol - meiosis ; GO:0007126 translesion pol - new term 'translesion synthesis' role in neurogenesis ; GO:0007399 DNA replication ; GO:0006260

gamma DNA-directed DNA polymerase activity ; GO:0003895 -->mitochondrial DNA replication ; GO:0006264

delta DNA polymerase activity ; GO:0003891 --> main pol at leading / lagging strand - DNA strand elongation ; GO:0006271 base excision repair ; GO:0006284 NT excision repair ; GO:0006289 mismatch rpr ; GO:0006298 DSBR ; GO:0006302 recomb pol - DNA recombination ; GO:0006310 3'-exonuclease - 3'-5' exonuclease activity ; GO:0008408

epsilon DNA polymerase activity ; GO:0003893 -->leading / lagging strand pol - DNA strand elongation ; GO:0006271 BER - base excision repair ; GO:0006284 recomb - DNA recombination ; GO:0006310 checkpoint control - ??? DNA replication checkpoint ; GO:0000076

eta - xeroderma pigmentosum variant pol accurate mismatch pol - mismatch repair ; GO:0006298 somatic hypermutation pol (strand-biased hot-spot A mutations)

somatic hypermutation of antibody genes ; GO:0016446 capable of both error-free and error-prone translesion synthesis

translesion synthesis ; GO:new error-free postreplication DNA repair ; GO:0042275 error-prone postreplication DNA repair ; GO:0042276 mutagenic bypass - bypass DNA synthesis ; GO:0019985 continues chain elongation - DNA strand elongation ; GO:0006271

iota - meiosis pol can incorporate opposite lesions - ie. translesion synth

• GO:new most error prone - error-prone DNA repair ; GO:0045020 violates Watson-Crick base pairing - mutagenesis ; GO:0006280 somatic hypermutation - somatic hypermutation of antibody genes ; GO:0016446 can replicate over 5MeC and T-T cyclobutane pyr, extend wrongly synth'd lesions - DNA strand elongation ; GO:0006271, bypass DNA synthesis ; GO:0019985 has 5'-deoxyribose phosphatase activity

kappa - deletion / base substitution pol low fidelity, moderate processivity strand biased hot-spot A mutations - mutagenesis ; GO:0006280 error-prone at abasic site, 8-oxoguanine - error-prone DNA repair ; GO:0045020 free at AAF adduct, the (-)-trans-anti-benzo(a)pyrene-N2-dG adduct

error-free DNA repair ; GO:0045021 somatic hypermutation - somatic hypermutation of antibody genes ; GO:0016446 spontaneous mutagenesis - mutagenesis ; GO:0006280

lambda - repair in meiosis, homol to pol beta has 5'-deoxyribose phosphatase activity DNA binding, nucleotide binding --> BER? DNA binding ; GO:0003677, nucleotide binding ; GO:0000166 ? repair during meiosis - DNA repair ; GO:0006281, meiosis ; GO:0007126

mu - homologous to template independent pol lymphoid formation pol somatic hypermutation of Ig genes? - somatic hypermutation of antibody genes ; GO:0016446 hypermutase? - mutagenesis ; GO:0006280 ? translesion DNA synthesis - translesion synthesis ; GO:new

sigma 1,2 - homol to pol beta both are sis ch/tid adhesion pols DNA synth during sis ch/tid cohesion - DNA replication ; GO:0006260 --> mitosis, ch/some segregation - mitotic sister chromatid separation ; GO:0016359 required for building connection btwn sis ch/tids - mitotic sister chromatid cohesion ; GO:0007064

zeta - developmental pol (nonredundant) cell proliferation pol - cell proliferation ; GO:0008283 mismatch extender pol - DNA strand elongation ; GO:0006271 somatic hypermutation pol - somatic hypermutation of antibody genes ; GO:0016446 the extender for the translesion products, doesn't actually insert them, tho. - TLS ; GO:new deoxycytidyl transferase activity - deoxycytidyl transferase activity ; GO:0017125 DNA repair and mutagenesis - mutagenesis ; GO:0006280, DNA repair ; GO:0006281

Original comment by: girlwithglasses

[gocentral]

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What is the status with this one?

I am in the process of annotating a polymerase (X family)

which has a preference for 5'-phosohate group for primer extension (as opposed to hydroxyl group)

this substrate preference seems to be a biochemical distinction which could be incorporated into GO function?

(this biochemical activity is associated with repair function...it seems to be associated with the beta gamma and mu types see PMID:16120966)

Original comment by: ValWood

[gocentral]

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This appears to be another biochemical distinction (ignoring the cell-type specific part of this definition which does not appear to be general, this activity appears to be template independent.....)

Introduction to TdT:

Terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase that adds non-germline encoded (N) nucleotides to the junctions between gene segments during somatic recombination in lymphocytes. This enzyme is distinct from other DNA polymerases in that it can add nucleotides to the 3? end of gene segments without the use of a template strand. Because TdT adds non-template encoded nucleotides to the junctions between gene segments, it contributes extensively to the junctional diversity of the third complementarity-determining region of lymphocyte receptors. Thus, TdT is important in the establishment of a combinatorially diverse lymphocyte repertoire.

Original comment by: ValWood

[gocentral]

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Hi Val I think this is still in limbo. That being said, I think there is a more basic principle here, namey, should we have the function ontology incorporate substrate preference. The driving force for cleaning up dodgy items in function appears to be strict adherance to the "Elemental activities, such as catalysis or binding, describing the actions of a gene product at the molecular level. A given gene product may exhibit one or more molecular functions.", and that a function can only describe a single reaction (otherwise it is a process). Another way of putting it is to ask what are we describing when we are descriving a catalytic activity? Is it the entire reaction (all components), or what happens at the active site? I think what we have done is somewhere in between. Perhaps we need to consider how the reaction is assayed. In this case, one would measure activity of all of them using template-driven dNTP incorporation; add to that "primer-dependent, template-driven dNTP incorporation I think for the moment, we are holding the status quo.

Original comment by: hdrabkin

[gocentral]

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Ages ago I did some work on this - finding out what processes various polymerases are involved in, any functions that they might have - but as Harold says, this item is currently in limbo. I don't want to do anything further on it until there's been more discussion on what should and shouldn't be included in function.

Original comment by: girlwithglasses

[gocentral]

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Hello,

I just want to add that pol alpha acts during the priming of DNA replication, which makes it (maybe) a different activity. See PMID 11165510 and SF item 1338479.

Pascale

Original comment by: pgaudet

[gocentral]

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My concern, however, is that if we define the activty as deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)

then it shouldn't matter when it occurs; it is the same reaction as defined by beta, or DNA-directed DNA polymerase activity. The "when" doesn't enter into the definition of the reaction catalyzed. A gene product that is an alpha DNA polymerase could be annotated to Function DNA-directed DNA polymerase activity and Process of DNA replication initiation (and maybe that needs of child : Priming, or someting along those lines.

Original comment by: hdrabkin

[gocentral]

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I have emailed the GO list proposing to merge the [greek letter] DNA polymerase activity terms with the parent 'DNA-directed DNA polymerase activity' (GO:0003887). That (a) is easy to do; (b) lets us keep existing annotations; and (c) is consistent with more recent policy on obsoleting versus merging versus rewriting definitions.

It'll be nice to have this one out of the way ... m

Original comment by: mah11

[gocentral]

• milestone: --> TermGenie
• assigned_to: nobody --> gomidori

Original comment by: mah11

[gocentral]

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note: as for many other similarly motivated merges, the names of the merged terms will be narrow synonyms of GO:0003887.

Original comment by: mah11

[gocentral]

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merges DONE!

Original comment by: mah11

[gocentral]

• status: open --> closed-fixed

Original comment by: mah11