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Let me review the main GO-CAM model now based on all the information I've gathered:

GO-CAM Model Review - gomodel:627d95ee00001988

Basic Information

  • Title: Regulation of Parp1 activity by Cgas, Setd7 and Riox1 (Mouse)
  • Taxon: Mouse (NCBITaxon:10090)
  • Status: Production
  • Primary reference: PMID:35210392

Model Overview

This GO-CAM model represents the regulatory pathway involving Setd7, Riox1, Sgf29, and Cgas in the control of Parp1 (poly(ADP-ribose) polymerase 1) activity during DNA repair in mouse. The model describes how these proteins interact to regulate DNA repair, particularly homologous recombination (HR) repair following DNA damage.

Key Molecular Components

  1. Setd7 (MGI:MGI:1920501) - Protein-lysine N-methyltransferase activity (GO:0016279)
  2. Riox1 (MGI:MGI:1919202) - 2-oxoglutarate-dependent dioxygenase activity (GO:0016706)
  3. Sgf29 (MGI:MGI:1922815) - Methylation-dependent protein binding (GO:0140034)
  4. Cgas (MGI:MGI:2442261) - Poly-ADP-D-ribose modification-dependent protein binding (GO:0160004)
  5. Parp1 (MGI:MGI:1340806) - NAD+-protein poly-ADP-ribosyltransferase activity (GO:0003950)

Pathway Description

Based on the model and literature, the pathway operates as follows:

  1. Setd7 methylates Cgas at K491
  2. Riox1 acts as a demethylase that removes the methylation at K491 of Cgas
  3. When Cgas is methylated (K491me), it interacts with Sgf29 (methylation reader protein)
  4. When Cgas is demethylated by Riox1, it can bind to poly-ADP-ribosylated Parp1 at DNA break sites
  5. The binding of demethylated Cgas to Parp1 prevents the recruitment of Timeless, inhibiting homologous recombination repair
  6. Thus, Riox1 negatively regulates DNA repair by enabling Cgas to interfere with Parp1's function

Causal Relationships in the Model

  • Setd7 (protein-lysine N-methyltransferase activity) positively regulates Sgf29 (methylation-dependent protein binding)
  • Riox1 (2-oxoglutarate-dependent dioxygenase activity) positively regulates Cgas (poly-ADP-D-ribose modification-dependent protein binding)
  • Sgf29 (methylation-dependent protein binding) negatively regulates Cgas (poly-ADP-D-ribose modification-dependent protein binding)
  • Cgas (poly-ADP-D-ribose modification-dependent protein binding) negatively regulates Parp1 (NAD+-protein poly-ADP-ribosyltransferase activity)

Model Assessment

Strengths

  1. The model accurately represents the molecular functions of each protein involved in the pathway.
  2. The causal relationships between the activities are well captured with appropriate RO predicates.
  3. The activities are connected in a way that is consistent with the described pathway in the primary literature.
  4. The model captures the key regulatory mechanisms involving protein methylation, demethylation, and protein-protein interactions.

Areas for Improvement

  1. Missing component: The model doesn't include Timeless protein, which is mentioned in the literature as a key component in the pathway (Cgas prevents Timeless recruitment by binding to Parp1).
  2. Cellular location information: While Cgas is annotated as occurring in the nucleus (GO:0005634), more detailed cellular location information for other proteins could enhance the model.
  3. Molecular complexes: Based on the GO-CAM guidelines for complex annotation, if specific subunits with known activities are involved, they should be represented individually, which this model does follow.

Consistency with Literature

The model is consistent with the primary literature (PMID:35210392), which describes how Riox1 demethylates cGAS K491me, facilitating the binding of cGAS to PARP1 and blocking HR repair. The paper explains the mechanism where RIOX1 expression governs the level of cGAS K491me, which in turn affects the interaction between cGAS and PARP1.

Recommendations

  1. Consider adding Timeless: Since Timeless plays a key role in the pathway described in the literature, it would enhance the model to include its activity and regulation.

  2. Add more cellular compartment information: Specify where these interactions are occurring, particularly for the DNA repair activities.

  3. Expand biological context: The model could benefit from more explicit connections to the higher-level biological processes like DNA damage response.

  4. Enhance evidence attribution: While the model includes PMID references, it would be beneficial to ensure that each causal relationship has appropriate evidence codes and references.

Conclusion

The GO-CAM model "Regulation of Parp1 activity by Cgas, Setd7 and Riox1" (gomodel:627d95ee00001988) is a high-quality representation of the regulatory pathway controlling Parp1 activity during DNA repair. It accurately captures the key molecular functions and causal relationships between proteins involved in this pathway, as described in the scientific literature. With a few minor enhancements, it could provide an even more comprehensive representation of this important cellular process.