#11349 NTR: DSB repair via alternative non homologous end joining

[rach_huntley]

NTR: "Double Strand Break repair via alternative non homologous end-joining"
or "Double Strand Break repair via microhomology-mediated end-joining".

Child of GO:0006302 (double strand break repair)

Synonyms: alt-NHEJ; MMEH; alternative non homologous end joining; microhomology-mediated end-joining

Possible definition: The repair of a double-strand break in DNA in which two broken DNA ends with small sections of homology (microhomology) are rejoined. Information at the DNA ends may be lost due to the modification of broken DNA ends. If the two ends are derived from different chromosomes, chromosomal translocation can occur resulting in mutated genes.

Described in http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107202/ and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430616/
See also: http://en.wikipedia.org/wiki/Microhomology-mediated_end_joining

Note, the new term is not the same as GO:0000724 (homologous recombination) as alt-NHEJ is not error-free and is also distinct from single strand annealing (GO:0045002) as evidenced in http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430616/

Thanks,
Rachael.

[Paola Roncaglia]

Hi Rachael,

Would your new term be a specific instance of
GO:0006303 double-strand break repair via nonhomologous end joining
("The repair of a double-strand break in DNA in which the two broken ends are rejoined with little or no sequence complementarity. Information at the DNA ends may be lost due to the modification of broken DNA ends.")
?

If yes, we may want to make the differentia a bit more evident in the def.
Or was that your intent with the last sentence "If the two ends are derived from different chromosomes, chromosomal translocation can occur resulting in mutated genes."

Thanks,

Paola

[rach_huntley]

Hi Paola,

I guess it could be a sub-type, but it depends what GO:0006303 is describing. This is from the second paper listed above: "Non-homologous end joining (NHEJ) is a major pathway of DSB repair, in which the ends are ligated without the use of extensive homology. NHEJ appears to comprise both classical-NHEJ and alternative-NHEJ (alt-NHEJ). Classical-NHEJ requires a number of factors important for V(D)J recombination, including the KU70/80 heterodimer (KU), XRCC4, Ligase IV, and DNA-PKcs...In contrast, alt-NHEJ appears to be independent of the above factors, and often results in a deletion with microhomology at the repair junction...Among these different subclasses of NHEJ, alt-NHEJ/MMEJ appears to play a significant role in the etiology of mutations that arise during cancer development and treatment." Is GO:0006303 describing classical-NHEJ or NHEJ in general? Also, microhomology is described as 5-25bp homology - is this little homology? I'm not sure.

The canonical/classical NHEJ pathway is well characterized and does not produce translocations. When the canonical pathway is disrupted then the effects of the alt-NHEJ pathway (translocations) become more apparent. It appears that both pathways can occur at the same time, but the canonical pathway suppresses translocations (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107202/ "Given that translocations appear to arise by alt-NHEJ even in the presence of the canonical pathway").

It seems that there are two distinct pathways (actually more if you consider single strand annealing and homology-directed repair (HDR/GC)), each are slightly mechanistically different (see the introduction and discussion of http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430616/).

Sorry, I've only just started reading about this!

Thanks,
Rachael.

[rach_huntley]

Hi Paola,

This paper is quite recent http://www.ncbi.nlm.nih.gov/pubmed/?term=24837021. It gives evidence that there are two separate pathways (classical-NHEJ and alternative-NHEJ) but suggests that the picture may be more complex than this, with different branches to each pathway (see Fig.8 for a summary).

Rachael.

[Paola Roncaglia]

Hi Rachael,

Thanks for providing further information. I think that the existing term, GO:0006303 double-strand break repair via nonhomologous end joining, may be considered a generic parent covering instances of classical/canonical as well as alternative NHEJ. The term is quite old and based on a 2000 paper (see fig. 2 here http://www.sciencedirect.com/science/article/pii/S0168952500020229). It has 202 manual annotations and it wouldn’t be straightforward to ‘split’ these into C-NHEJ and A-NHEJ. So I suggest we keep GO:0006303 double-strand break repair via nonhomologous end joining as is, and add two children terms for C-NHEJ and A-NHEJ. (I would stop there - we could always add further subclasses if needed when they’re better characterized.) Let me know if you’d disagree with this suggestion.

Thanks,
Paola.

[rach_huntley]

Hi Paola,

I think your suggestion is good. Since the alternative pathway has only relatively recently been described, there could be annotations that looked like they were classical NHEJ but were in fact the alternative pathway. I also haven't come across very much evidence for further subclasses, so agree that we shouldn't add anything else in just yet.

Thanks for your help.
Rachael.

[Paola Roncaglia]

Hi and thanks for your feedback. I’ll get back to this next week as I’ll be on leave for a few days. Thanks for your patience!

Paola

[Paola Roncaglia]

Hi Rachael,

Finally getting to do this! I'm also going to update your entry in the GO.curator_dbxrefs file. Should you appear simply as BHF-UCL, or does your project have a specific name please? (E.g. Becky is entered as UCL-Parkinson's UK Annotation Project.)

Thanks,
Paola

[rach_huntley]

Hi Paola,

Thanks for this. Can you set my dbxrf the same as for Nancy Campbell and Ruth, which I assume is BHF-UCL?

Thanks,
Rachael.

[Paola Roncaglia]

Thanks Rachael,

Your affiliation is now updated. More soon...

Paola

[Paola Roncaglia]

Hi Rachael, all done now:

• expanded def and dbxrefs of GO:0006303 double-strand break repair via nonhomologous end joining;
• added GO:0097680 double-strand break repair via classical nonhomologous end joining;
• added GO:0097681 double-strand break repair via alternative nonhomologous end joining.

Full details in the diff below. Thanks,
Paola

-def: "The repair of a double-strand break in DNA in which the two broken ends are rejoined with little or no sequence complementarity. Information at the DNA ends may be lost due to the modification of broken DNA ends." [PMID:10827453]
+def: "The repair of a double-strand break in DNA in which the two broken ends are rejoined with little or no sequence complementarity. Information at the DNA ends may be lost due to the modification of broken DNA ends. This term covers instances of separate pathways, called classical (or canonical) and alternative nonhomologous end joining (C-NHEJ and A-NHEJ). These in turn may further branch into sub-pathways, but evidence is still unclear." [GOC:rph, PMID:10827453, PMID:24837021]

[Term]
+id: GO:0097680
+name: double-strand break repair via classical nonhomologous end joining
+namespace: biological_process
+def: "An instance of double-strand break repair via nonhomologous end joining that requires a number of factors important for V(D)J recombination, including the KU70/80 heterodimer (KU), XRCC4, ligase IV, and DNA-PKcs in mammals. It does not produce translocations (as opposed to the alternative nonhomologous end joining)." [GOC:rph, PMID:18584027]
+synonym: "C-NHEJ" RELATED []
+synonym: "canonical nonhomologous end joining" EXACT []
+is_a: GO:0006303 ! double-strand break repair via nonhomologous end joining

+[Term]
+id: GO:0097681
+name: double-strand break repair via alternative nonhomologous end joining
+namespace: biological_process
+def: "An instance of double-strand break repair via nonhomologous end joining that is independent of factors important for V(D)J recombination (as opposed to classical nonhomologous end joining). It often results in a deletion with microhomology (i.e. 5-25bp homology) at the repair junction. Among different subclasses of nonhomologous end joining (NHEJ), alternative NHEJ appears to play a significant role in the etiology of mutations that arise during cancer development and treatment." [GOC:rph, http://en.wikipedia.org/wiki/Microhomology-mediated_end_joining, PMID:18584027, PMID:21655080]
+synonym: "A-NHEJ" RELATED []
+synonym: "alt-NHEJ" RELATED []
+synonym: "double-strand break repair via microhomology-mediated end joining" EXACT []
+synonym: "MMEJ" RELATED []
+is_a: GO:0006303 ! double-strand break repair via nonhomologous end joining