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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
KAT5 histone acetyltransferase mutations in cancer cells
Kimberly L Hardison1, Tila M Hawk1, Renee A Bouley1
1The Ohio State University.
Abstract:
Cancer cells are characterized by accumulation of mutations due to improperly repaired DNA damage. The DNA double strand break is one of the most severe form of damage and several redundant mechanisms have evolved to facilitate accurate repair. During DNA replication and in mitosis, breaks are primarily repaired by homologous recombination which is facilitated by several genes. Key to this process is the breast cancer susceptibility genes BRCA1 and BRCA2 as well as the accessory RAD52 gene. Proper chromatin remodeling is also essential for repair and the KAT5 histone acetyltransferase facilitates histone removal at the break. Here we undertook a pan cancer analysis to investigate mutations within the KAT5 gene in cancer cells. We employed two standard artificial algorithms to classify mutations as either driver (CHASMPlus algorithm) or pathogenic (VEST4 algorithm). We find that most predicted driver and disease-causing mutations occur in the catalytic site or within key regulatory domains. In silico analysis of protein structure using AlphaFold shows that these mutations are likely to destabilize the function of KAT5 or interactions with DNA or its other partners. The data presented here, although preliminary, could be used to inform clinical strategies.
Insights
This study analyzes KAT5 gene mutations in cancer, finding that critical mutations often occur in functional domains, potentially disrupting DNA repair pathways. These findings may inform future cancer treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer cells accumulate mutations from unrepaired DNA damage, particularly DNA double-strand breaks.
- Homologous recombination is a key repair mechanism, involving genes like BRCA1, BRCA2, and RAD52.
- Chromatin remodeling, facilitated by KAT5 histone acetyltransferase, is crucial for DNA repair.
Purpose of the Study:
- To investigate mutations within the KAT5 gene across various cancer types.
- To classify identified KAT5 mutations as driver or pathogenic using computational algorithms.
- To analyze the structural and functional impact of these mutations on KAT5 protein.
Main Methods:
- Pan-cancer analysis of KAT5 gene mutations.
- Application of CHASMPlus and VEST4 algorithms for mutation classification.
- In silico protein structure analysis using AlphaFold.
Main Results:
- Most predicted driver and pathogenic KAT5 mutations are located in the catalytic site or regulatory domains.
- In silico analysis suggests these mutations destabilize KAT5 function or its interactions.
- Preliminary data highlights the potential impact of KAT5 mutations on cancer development.
Conclusions:
- KAT5 mutations in key functional regions may impair its role in DNA repair.
- Computational predictions indicate a significant functional consequence of identified mutations.
- Further research could leverage these findings for clinical applications in cancer therapy.
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