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627d95ee00002030 Activation of PARP2 activity by HPF1 during DNA repair Human

Based on the above information, I'll now perform a thorough review of GO-CAM model "gomodel:627d95ee00002030" titled "Activation of PARP2 activity by HPF1 during DNA repair (Human)".

GO-CAM Model Review: Activation of PARP2 activity by HPF1 during DNA repair (Human)

Overview

This model (gomodel:627d95ee00002030) represents the activation of PARP2 (Poly(ADP-ribose) polymerase 2) by HPF1 (Histone PARylation factor 1) during DNA repair in humans. The model consists of 4 activities and describes how these proteins interact to enable ADP-ribosylation at DNA damage sites.

Model Components

The model contains the following molecular functions and proteins:

  1. PARP2 (UniProtKB:Q9UGN5)
  2. Damaged DNA binding (GO:0003684)
  3. NAD+-protein-serine ADP-ribosyltransferase activity (GO:0140805)

  4. NAD+-protein poly-ADP-ribosyltransferase activity (GO:0003950)

  5. HPF1 (UniProtKB:Q9NWY4)

  6. Protein ADP-ribosyltransferase-substrate adaptor activity (GO:0140768)

Model Accuracy and Biological Content

The model effectively captures the current scientific understanding of how PARP2 is activated by HPF1 during DNA repair, as supported by the literature:

  1. PARP2's DNA binding ability: The model correctly shows that PARP2 has damaged DNA binding activity (GO:0003684), which occurs at the site of DNA damage (GO:0090734). This is consistent with the literature showing that PARP2 recognizes and binds to DNA breaks, particularly 5'-phosphorylated DNA breaks.

  2. HPF1's role as an adaptor: The model appropriately represents HPF1 as having protein ADP-ribosyltransferase-substrate adaptor activity (GO:0140768). This accurately reflects HPF1's function in switching PARP2's amino acid specificity from glutamate/aspartate to serine residues.

  3. Causal relationships: The model uses RO:0002629 (directly positively regulates) to show how damaged DNA binding by PARP2 leads to NAD+-protein-serine ADP-ribosyltransferase activity. It also correctly shows how HPF1 activity directly positively regulates PARP2's ADP-ribosyltransferase activity.

  4. Sequential activity flow: The model captures the sequential flow of activity - from DNA damage binding by PARP2, to HPF1 regulation of PARP2, to the serine ADP-ribosylation activity, and finally to poly-ADP-ribosylation.

Areas for Improvement or Considerations

  1. Duplicate causal association: There appears to be a duplicate causal association from PARP2's damaged DNA binding activity to its NAD+-protein-serine ADP-ribosyltransferase activity. One of these associations lacks evidence, which should be addressed.

  2. Conformational changes: The model does not explicitly represent the conformational changes that PARP2 undergoes upon DNA binding, which are critical for its activation as detailed in the PMID:34108479 paper. This includes the reorganization of the regulatory domain (RD) that allows NAD+ binding and HPF1 interaction.

  3. Temporal aspects: While the model shows the correct sequence of events, it might benefit from additional details about how HPF1 initiates serine ADP-ribosylation but also restricts the length of poly-ADP-ribose chains, as mentioned in the literature.

  4. Target representation: The model doesn't explicitly show the targets of ADP-ribosylation (such as histones), which would provide a more complete picture of the process.

Compliance with GO-CAM Best Practices

The model follows GO-CAM best practices by:

  1. Using appropriate molecular function terms for each protein
  2. Properly representing the causal relationships between activities
  3. Including cellular locations (site of DNA damage, GO:0090734)
  4. Including biological process context (DNA repair, GO:0006281 and DNA damage response, GO:0006974)
  5. Using evidence codes and literature references to support assertions

Final Assessment

This GO-CAM model (gomodel:627d95ee00002030) is scientifically accurate and well-constructed. It successfully captures the key aspects of PARP2 activation by HPF1 at DNA damage sites.

The model could be enhanced by: 1. Removing the duplicate causal association 2. Adding more detail about the conformational changes in PARP2 3. Including the targets of ADP-ribosylation (histones and other proteins) 4. Providing more detail about how HPF1 both enables serine-specific ADP-ribosylation and regulates poly-ADP-ribose chain length

Overall, this is a high-quality model that accurately represents our current understanding of the biological process and complies with GO-CAM best practices.