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617b481400003575 SP RNF169

Now, let me review the GO-CAM model with ID gomodel:617b481400003575 in detail.

GO-CAM Model Review for gomodel:617b481400003575

Model Title: SP-RNF169

Summary of the Model

This model represents a molecular pathway involving DYRK1A (Q13627), RNF169 (Q8NCN4), TP53BP1 (Q12888), and UIMC1/RAP80 (Q96RL1) in human cells (taxon: 9606). The model describes how DYRK1A protein serine kinase activity positively regulates RNF169's ubiquitin-modified histone reader activity, which in turn negatively regulates both TP53BP1 and UIMC1/RAP80 ubiquitin-modified histone reader activities.

Review of Molecular Activities and Causal Associations

  1. DYRK1A (UniProtKB:Q13627)
  2. Molecular Function: Protein serine kinase activity (GO:0106310)
  3. Causal Association: Directly positively regulates (RO:0002629) RNF169's ubiquitin-modified histone reader activity
  4. Evidence: ECO:0000314 (direct assay evidence) from PMID:30773093
  5. Contributor: https://orcid.org/0000-0001-7646-0052

  6. Date: 2021-11-18

  7. RNF169 (UniProtKB:Q8NCN4)

  8. Molecular Function: Ubiquitin-modified histone reader activity (GO:0061649)
  9. Occurs In: Site of double-strand break (GO:0035861)
  10. Part Of: Double-strand break repair via homologous recombination (GO:0000724)
  11. Causal Association:
    • Directly negatively regulates (RO:0002630) TP53BP1's ubiquitin-modified histone reader activity
    • Directly negatively regulates (RO:0002630) UIMC1/RAP80's ubiquitin-modified histone reader activity
  12. Evidence: ECO:0000314 (direct assay evidence) from PMID:22492721 and PMID:30104380
  13. Contributor: https://orcid.org/0000-0001-7646-0052

  14. Date: 2021-11-18

  15. TP53BP1 (UniProtKB:Q12888)

  16. Molecular Function: Ubiquitin-modified histone reader activity (GO:0061649)
  17. Occurs In: Site of double-strand break (GO:0035861)
  18. Part Of: Double-strand break repair via nonhomologous end joining (GO:0006303)
  19. Evidence: ECO:0000314 (direct assay evidence) from PMID:22492721 and PMID:23333306
  20. Contributor: https://orcid.org/0000-0001-7646-0052

  21. Date: 2021-11-18

  22. UIMC1/RAP80 (UniProtKB:Q96RL1)

  23. Molecular Function: Ubiquitin-modified histone reader activity (GO:0061649)
  24. Occurs In: Site of double-strand break (GO:0035861)
  25. Part Of: Double-strand break repair via nonhomologous end joining (GO:0006303)
  26. Evidence: ECO:0000314 (direct assay evidence) from PMID:22492721
  27. Contributor: https://orcid.org/0000-0001-7646-0052
  28. Date: 2021-11-18

Automated Changes

The model shows the following automated changes: - "RO:0002212 replaced by RO:0002630" (2023-03-16) - "RO:0002213 replaced by RO:0002629" (2023-03-16)

These changes updated the relation terms to use the more specific "directly positively/negatively regulates" predicates.

Assessment and QC

Biological Content Consistency

The model represents a well-substantiated pathway based on research published in PMID:30773093 and PMID:22492721. The model captures how: 1. DYRK1A phosphorylates RNF169 (in response to DNA damage) 2. This phosphorylation enhances RNF169's ability to bind to ubiquitylated histones at DNA damage sites 3. RNF169 then competes with and inhibits TP53BP1 and UIMC1/RAP80 from binding to the same modified chromatin 4. This competition influences the choice between homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair pathways

The papers clearly support that RNF169 functions in homologous recombination (HR) repair, while TP53BP1 and UIMC1/RAP80 promote non-homologous end joining (NHEJ).

GO-CAM Best Practices

The model follows GO-CAM best practices in several ways: 1. Each activity is enabled by a single gene product 2. Causal connections use appropriate relation terms (directly positively/negatively regulates) 3. Activities are properly contextualized with subcellular location (site of double-strand break) 4. Activities are appropriately linked to biological processes (different DNA repair pathways) 5. Evidence codes and references are properly included

Opportunities for Improvement

While the model is scientifically accurate and well-structured, I suggest a few improvements:

  1. Completeness: The model could be expanded to include:
  2. The mechanism by which DYRK1A is activated in response to DNA damage
  3. The specific phosphorylation sites on RNF169 (S368 and S403) mentioned in PMID:30773093

  4. The downstream effects of pathway choice (HR vs. NHEJ) on DNA repair outcomes

  5. Activity Annotation:

  6. DYRK1A is annotated with "protein serine kinase activity" which is appropriate, but could be more specifically annotated with "protein serine/threonine/tyrosine kinase activity" (GO:0004712) based on UniProt annotation, though this may be less relevant for this specific context.

Parsimoniousness and Readability

The model is parsimonious and readable. It clearly illustrates the competition between RNF169 and both TP53BP1 and UIMC1/RAP80 for binding to ubiquitylated histones at DNA damage sites, which is the key regulatory mechanism described in the underlying literature.

Conclusion

Overall, this GO-CAM model (gomodel:617b481400003575) accurately represents the pathway described in the literature where DYRK1A phosphorylates RNF169 to enhance its ability to compete with TP53BP1 and UIMC1/RAP80 for binding to ubiquitylated histones at DNA damage sites, thereby influencing DNA repair pathway choice.

The model follows GO-CAM best practices, uses appropriate GO terms, relations, and evidence codes, and effectively captures the biological mechanism described in the literature. While there are minor opportunities for expansion, the model is scientifically accurate, well-structured, and parsimonious.