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617b481400000460 KAT5 involvement in DNA repair via homologous recombination Human

Now, let me review the GO-CAM model in detail. Based on the information I've gathered, I'll analyze the model "KAT5 involvement in DNA repair via homologous recombination (Human)" (gomodel:617b481400000460).

GO-CAM Model Review: KAT5 involvement in DNA repair via homologous recombination (Human)

Overview:

This GO-CAM model represents the role of KAT5 (TIP60) in DNA double-strand break repair, specifically how it influences the choice between DNA repair pathways (homologous recombination vs. non-homologous end joining) through its interactions with histone modifications and 53BP1.

Scientific Content Assessment:

The model captures several key molecular activities and their causal relationships:

  1. RNF168 (UniProtKB:Q8IYW5) performs histone H2AK15 ubiquitin ligase activity (GO:0140858) at sites of double-strand breaks (GO:0035861), which provides input for TP53BP1 ubiquitin-modified histone reader activity and DNA-binding transcription factor activity.

  2. KAT5 (UniProtKB:Q92993) performs histone H2A acetyltransferase activity (GO:0043998) at sites of double-strand breaks, which maintains a regulatory relationship with TP53BP1 methylated histone binding activity.

  3. MBTD1 (UniProtKB:Q05BQ5) performs methylated histone binding (GO:0035064) and directly negatively regulates TP53BP1 binding to methylated histones.

  4. EPC1 (UniProtKB:Q9H2F5) performs chromatin-protein adaptor activity (GO:0140463) and directly positively regulates MBTD1 activities.

  5. TP53BP1 (UniProtKB:Q12888) performs both methylated histone binding (GO:0035064) and ubiquitin-modified histone reader activity (GO:0061649).

  6. Additional regulatory proteins: PIAS4 and SENP3 regulate KAT5 through sumoylation processes.

Pathway Logic:

The model correctly depicts the competition between homologous recombination (HR) and non-homologous end joining (NHEJ) pathways at double-strand breaks:

  • The TIP60 complex (KAT5) promotes HR by:
  • Acetylating H2AK15, which prevents ubiquitination of this site by RNF168

  • Using MBTD1 to compete with 53BP1 for binding to H4K20me2

  • 53BP1 promotes NHEJ by:

  • Binding to H4K20me2 via its Tudor domain
  • Binding to H2AK15ub via its UDR motif

Model Strengths:

  1. The model accurately captures the bivalent chromatin recognition system of 53BP1 (binding to both H4K20me2 and H2AK15ub).

  2. It correctly represents the antagonistic relationship between KAT5 and 53BP1, where KAT5 promotes HR by interfering with 53BP1 binding.

  3. The regulatory relationships use appropriate causal predicates (RO:0002413 "provides input for", RO:0002629 "directly positively regulates", and RO:0002630 "directly negatively regulates").

  4. The model incorporates MBTD1 as a key component of the TIP60 complex that competes with 53BP1 for H4K20me2 binding.

  5. The inclusion of EPC1 as an adaptor protein for MBTD1 is supported by the literature.

  6. The model shows how PIAS4 and SENP3 regulate KAT5 activity, reflecting the dynamic regulation of repair pathway choice.

Suggestions for Improvement:

  1. Representation of the NuA4/TIP60 Complex: While the model shows KAT5 and some components, the full TIP60 complex isn't explicitly represented. According to best practices for complex annotation, using GO:0035267 (NuA4 histone acetyltransferase complex) might be appropriate in some places rather than individual proteins if the specific activity-carrying subunits aren't clearly identified.

  2. Cell Cycle Regulation: The model could be expanded to include cell cycle-dependent regulation of repair pathway choice. During S/G2 phases, HR is favored, while NHEJ predominates in G1.

  3. Bi-directional Process: It would be valuable to explicitly show that H2AK15 is a site of competition between ubiquitination (by RNF168) and acetylation (by KAT5), which directly impacts 53BP1 recruitment.

  4. Acetylation Target Specification: The histone H2A acetyltransferase activity (GO:0043998) could be more specifically annotated as H2AK15 acetyltransferase activity if that term is available, to better reflect the site-specific nature of this mechanism.

  5. Biological Process Annotation: The model correctly shows the part_of relationships to double-strand break repair processes (GO:0000724 and GO:0006303), but could potentially benefit from explicitly showing the antagonistic relationship between these processes.

Technical/Quality Issues:

  1. All activities and relationships in the model are properly supported with evidence codes and PMID references.

  2. The subcellular localization is consistently annotated as "site of double-strand break" (GO:0035861).

  3. I noticed the use of RO:0012010 in one causal association, which is not among the standard predicates listed in your guidelines (which include RO:0002413, RO:0002629, RO:0002630, RO:0002304, and RO:0002305). This should be checked for consistency.

Conclusion:

The GO-CAM model "KAT5 involvement in DNA repair via homologous recombination (Human)" is scientifically accurate and effectively represents the current understanding of how KAT5/TIP60 influences DNA repair pathway choice. It properly captures the competition between KAT5 and 53BP1 for binding to modified histones at double-strand breaks, and how this affects the choice between HR and NHEJ repair mechanisms.

The model follows most GO-CAM best practices for representing molecular activities, causal relationships, and cellular context. With a few minor refinements, particularly in the representation of protein complexes and the competitive relationship between repair pathways, this model could provide an even more comprehensive representation of this important biological process.