start of DNA replication

gocentral commented 10 years ago

When does DNA replication start? I think it starts with the binding of ORC recognition proteins to the DNA forming a complex. I also take "start", "begin" to be a synonym of "initiates", and starting implying parthood.

This is of course what we have:

DNA replication: http://amigo2.geneontology.org/cgi-bin/amigo2/amigo/term/GO:0006260 "...DNA replication begins when specific sequences, known as origins of replication, are recognized and bound by initiation proteins...."

Minor point: Is there a way to define this using GO terms rather than the vague "initiation protein"?

But it's less clear in other GO definitions, where the process of initiation is mentioned. This seems a bit fuzzy as to temporal boundaries, although I would take "initiation" to be at the start. For example:

DNA replication preinitiation complex assembly: http://amigo2.geneontology.org/cgi-bin/amigo2/amigo/term/GO:0071163 "The aggregation, arrangement and bonding together of a set of components to form the DNA replication preinitiation complex, a protein-DNA complex that is assembled at eukaryotic DNA replication origins _immediately prior to_ the initiation of DNA replication, by the assembly of additional proteins onto an existing prereplicative complex"

The def makes it sound like this happens prior to DNA replication, but it is (correctly) asserted as part_of replication (is this correct - preinitiation complex assembly is preceded by prereplicative complex assembly, and prereplicative complex assembly is the process that RO:starts DNA replication? Does every preinitiation complex derive_from some prepreplicative complex?).

Maybe the def should be modified: change "immediately prior to the initiation of" to "as part of"?

(also: s/prereplicative/pre-replicative/)

initiation has its own class in GO, but this is defined vaguely: http://amigo2.berkeleybop.org/cgi-bin/amigo2/amigo/term/GO:0006270 "The process in which DNA-dependent DNA replication is started; this involves the separation of a stretch of the DNA double helix, the recruitment of DNA polymerases and the initiation of polymerase action"

Does the "this" refer to the initiation or the DNA replication as a whole? What are the defining start and end events of initiation? No ordering is given. Terms like "recrutiment of DNA polymerase" doesn't seem to correspond to the existing terms in the GO.

There are no part children of initiation. But isn't GO:0036388 pre-replicative complex assembly always part of initiation? Do we need a part_of here?

Would it be correct to define initiation as starting with ORC binding, encompassing various stages of complex assembly depending on species, and ending with... DNA unwinding? (http://amigo2.geneontology.org/cgi-bin/amigo2/amigo/term/GO:0006268)

Reported by: cmungall

Original Ticket: geneontology/ontology-requests/10401

gocentral commented 10 years ago

Relevant recent review (April 2013) which I still need to read:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657122/?report=classic

Original comment by: tberardini

gocentral commented 10 years ago

assigned_to: Tanya Berardini

Original comment by: tberardini

gocentral commented 10 years ago

Former replication-ologist here, so I can't resist horning in ;)

We asked a very similar question about a year ago in [ontology-requests:9708] (now #9913), which is still open. Also see the ticket referred to in 9708, [ontology-requests:9634] (now #9841) - it mentions some other potentially useful reviews.

Would it be correct to define initiation as starting with ORC binding ..

Most assuredly not -- ORC is bound to origins throughout the cell cycle; iirc it's really only displaced briefly to make room for the replication machinery and re-binds well before replication is complete. It's one of the well-established things in the field that ORC binding is necessary but NOT sufficient for initiation. (This is the most important thing I had to pipe up to say-- we do need a better start point defined, but ORC binding is NOT IT.)

I think the major sticking point for the older ticket is that in eukaryotes, it's (relatively) easy to describe a series of steps, many of which are protein complex assembly processes, that take place when replication initiates, and the order in which they happen. The review Tanya mentioned is one of many that lay the steps out neatly. But it's been much harder to pinpoint which of the steps should be deemed initiation, and, in turn, which is the start of initiation. It looks like we got close in the comments on the other ticket, though -- it's most likely either phosphorylation of some pre-RC proteins or Cdc45+GINS binding, i.e. the steps that convert pre-RC to preIC. Probably just need to pin down the order of those two steps and then decide which one is start of initiation.

Other points:

Is there a way to define [DNA replication] using GO terms rather than the vague "initiation protein"?

It might also be a bit challenging, but doable, to find words to use in place of "initiation protein(s)", although whatever is used will have to accommodate the bacterial system (much simpler - DnaA binds & melts DNA, other proteins arrive, and off you go) as well as archaeal and eukaryotic. I don't know if there's a GO term for DnaA ..? Or do you mean it should refer to the initiation BP def?

Maybe the [GO:0071163] def should be modified: change "immediately prior to the initiation of" to "as part of"?

Probably ok - should be resolved by figuring out where initiation really starts, as noted above.

Does the "this" [in the initiation def] refer to the initiation or the DNA replication as a whole?

Appears to refer to initiation rather than the rest of replication, because it doesn't mention elongation or termination. In the older tickets, I was leaning towards saying initiation ends with the synthesis of the first primers, so if you do go with that end point, it's correct to include polymerase recruitment and first polymerase activity in initiation. I agree that the def needs editing in any case!

cheers, m

Original comment by: mah11

gocentral commented 10 years ago

Aha I had a note on my To Do list to ask about this ;)

So "phosphorylation of some pre-RC proteins or Cdc45+GINS binding" was is the start of replication.

Would this make "GO:0036388 pre-replicative complex assembly" not part of DNA replication? Currently it is. However, ontologically this seems wrong because, DNA replication is NOT regulated by these events, and if the processes which regulate "pre-replicative complex assembly" become propagated to "regulation of DNA replication" that would be incorrect.

It seems that most people would intuitively expect pre-replicative complex assembly to be part of replication though?

Perhaps pre-replicative complex assembly should only be is_a "protein complex assembly"

v

Original comment by: ValWood

gocentral commented 10 years ago

Very interesting discussion and one that could go on a very long time. I'm wondering what we can do, if anything, to improve the ontology sooner rather than later.

Original comment by: tberardini

gocentral commented 10 years ago

Some concrete steps:

Draw some kind of temporal diagram with starts and ends of subprocesses clearly marked and use this as our starting point (would be easier if we were sitting around a whiteboard)
Add starts_with, has_part and ends_with relationships (in main ontology or auxhiliary). Use reasoning to check for inconsistencies
(more generally, and longer term) try and use a concise well defined vocabulary in GO text definitions, use standard phrases for initiation etc, use existing GO terms and OBO terms as strings in the definition (where this does not interfere with flow)

I think this is a good candidate for "lego-ization"

Original comment by: cmungall

gocentral commented 10 years ago

We could try the whiteboard approach at JGI one of these days. We'd need a little prep work but it would be worth it.

Original comment by: tberardini

gocentral commented 10 years ago

Chris - does the work we did to model DNA replication cover what you wanted to get at with this SF item? If not, what should we/I do complete the task?

Original comment by: tberardini

gocentral commented 10 years ago

Did we complete it? If so we should get it into the core ontology & this should resolve the item

On 21 Feb 2014, at 15:49, Tanya Berardini wrote:

Chris - does the work we did to model DNA replication cover what you wanted to get at with this SF item? If not, what should we/I do complete the task?

\ [ontology-requests:#10401] start of DNA replication**

Status: open Created: Fri Sep 27, 2013 04:27 PM UTC by Chris Mungall Last Updated: Mon Oct 14, 2013 07:25 PM UTC Owner: Tanya Berardini

When does DNA replication start? I think it starts with the binding of ORC recognition proteins to the DNA forming a complex. I also take "start", "begin" to be a synonym of "initiates", and starting implying parthood.

This is of course what we have:

DNA replication: http://amigo2.geneontology.org/cgi-bin/amigo2/amigo/term/GO:0006260 "...DNA replication begins when specific sequences, known as origins of replication, are recognized and bound by initiation proteins...."

Minor point: Is there a way to define this using GO terms rather than the vague "initiation protein"?

But it's less clear in other GO definitions, where the process of initiation is mentioned. This seems a bit fuzzy as to temporal boundaries, although I would take "initiation" to be at the start. For example:

DNA replication preinitiation complex assembly: http://amigo2.geneontology.org/cgi-bin/amigo2/amigo/term/GO:0071163 "The aggregation, arrangement and bonding together of a set of components to form the DNA replication preinitiation complex, a protein-DNA complex that is assembled at eukaryotic DNA replication origins _immediately prior to_ the initiation of DNA replication, by the assembly of additional proteins onto an existing prereplicative complex"

The def makes it sound like this happens prior to DNA replication, but it is (correctly) asserted as part_of replication (is this correct - preinitiation complex assembly is preceded by prereplicative complex assembly, and prereplicative complex assembly is the process that RO:starts DNA replication? Does every preinitiation complex derive_from some prepreplicative complex?).

Maybe the def should be modified: change "immediately prior to the initiation of" to "as part of"?

(also: s/prereplicative/pre-replicative/)

initiation has its own class in GO, but this is defined vaguely: http://amigo2.berkeleybop.org/cgi-bin/amigo2/amigo/term/GO:0006270 "The process in which DNA-dependent DNA replication is started; this involves the separation of a stretch of the DNA double helix, the recruitment of DNA polymerases and the initiation of polymerase action"

Does the "this" refer to the initiation or the DNA replication as a whole? What are the defining start and end events of initiation? No ordering is given. Terms like "recrutiment of DNA polymerase" doesn't seem to correspond to the existing terms in the GO.

There are no part children of initiation. But isn't GO:0036388 pre-replicative complex assembly always part of initiation? Do we need a part_of here?

See also http://en.wikipedia.org/wiki/DNA_replication#Initiation

Would it be correct to define initiation as starting with ORC binding, encompassing various stages of complex assembly depending on species, and ending with... DNA unwinding? (http://amigo2.geneontology.org/cgi-bin/amigo2/amigo/term/GO:0006268)

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Original comment by: cmungall

gocentral commented 10 years ago

I thought we had covered all the basics. Will check with David.

Original comment by: tberardini

gocentral commented 10 years ago

Midori asked about the DnaA terms:

Yes, I curated the GO:1990101 DnaA-oriC complex and related 'initiation' and 'replication' complexes for E.coli (which are also generally true for other prokaryotes) a while ago in the complex portal and in GO. I recall having a discussion with the EBI editors before we committed the terms. It is likely that we also tweaked the one or other MF or BP term. I think Becky had the 'pleasure'!

Birgit

Original comment by: bmeldal

pgaudet commented 1 year ago

Minor point: Is there a way to define this using GO terms rather than the vague "initiation protein"?

Changed "initiation protein" to "origin recognition complex", which is a GO CC.

DNA replication preinitiation complex assembly: http://amigo2.geneontology.org/cgi-bin/amigo2/amigo/term/GO:0071163 "The aggregation, arrangement and bonding together of a set of components to form the DNA replication preinitiation complex, a protein-DNA complex that is assembled at eukaryotic DNA replication origins immediately prior to the initiation of DNA replication, by the assembly of additional proteins onto an existing prereplicative complex"

The def makes it sound like this happens prior to DNA replication, but it is (correctly) asserted as part_of replication (is this correct - preinitiation complex assembly is preceded by prereplicative complex assembly, and prereplicative complex assembly is the process that RO:starts DNA replication? Does every preinitiation complex derive_from some prepreplicative complex?).

Maybe the def should be modified: change "immediately prior to the initiation of" to "as part of"?

Changed.

GO:0006270 'DNA replication initiation' Would it be correct to define initiation as starting with ORC binding, encompassing various stages of complex assembly depending on species, and ending with... DNA unwinding? (http://amigo2.geneontology.org/cgi-bin/amigo2/amigo/term/GO:0006268) See also http://en.wikipedia.org/wiki/DNA_replication#Initiation

Changed definition from "The process in which DNA-dependent DNA replication is started; this begins with the ATP dependent loading of an initiator complex onto the DNA, this is followed by DNA melting and helicase activity. In bacteria, the gene products that enable the helicase activity are loaded after the initial melting and in archaea and eukaryotes, the gene products that enable the helicase activity are inactive when they are loaded and subsequently activate." [ISBN:071673706X, ISBN:0815316194, PMID:28209641]

to "The process in which DNA-dependent DNA replication is started; it begins when specific sequences, known as origins of replication, are recognized and bound by the origin recognition complex, followed by DNA unwinding." [PMID:28209641]

geneontology / go-ontology

start of DNA replication #10596