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Updated: Aug 1, 2025
Visualization of DNA Repair Proteins Interaction by Immunofluorescence
Published on: June 26, 2020
Acetylation of MLH1 by CBP increases cellular DNA mismatch repair activity
Mu Zhang1, Jiawei Zhao1, Peter M Glazer2
1Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, 4100 John R. St., Detroit, MI 48201, USA.
Abstract:
The DNA mismatch repair (MMR) proteins recognize and repair DNA base pair mismatches and insertions/deletions of DNA that have occurred during DNA replication. Additionally, they are involved in regulation of the DNA damage response, including cell cycle checkpoints and apoptosis. Therefore, regulation of these proteins is essential for maintaining genomic integrity. It has been recognized that post-translational modifications, such as phosphorylation, ubiquitination, and acetylation, are being used as an important means to regulate the functions and stability of MMR proteins. Here, we report that a histone acetyltransferase CREB binding protein (CBP) interacts with and acetylates MLH1, a component of the MutLα complex (MLH1-PMS2). Moreover, CBP stabilizes MLH1 by preventing it from degradation via the ubiquitin-proteasome degradation pathway. Consistently, acetylation induced by a pan-histone deacetylase inhibitor, Trichostatin A, promotes the assembly between the MutSα (MSH2-MSH6) and MutLα complexes. Furthermore, overexpression of CBP enhances MMR activities in cells. Overall, our results suggest a novel role of CBP in prolonging MLH1 stability and enhancing MutSα-MutLα complex formation, leading to increased cellular MMR activity.
Insights
The CREB binding protein (CBP) enhances DNA repair by acetylating and stabilizing MLH1, a key protein in the DNA mismatch repair (MMR) pathway. This stabilization boosts MMR activity, crucial for maintaining genomic integrity.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- DNA mismatch repair (MMR) proteins are critical for genomic integrity, correcting replication errors.
- Post-translational modifications regulate MMR protein function and stability.
- Acetylation is an important modification for MMR protein regulation.
Purpose of the Study:
- To investigate the role of histone acetyltransferase CREB binding protein (CBP) in regulating DNA mismatch repair (MMR).
- To determine if CBP interacts with and modifies MLH1, a component of the MutLα complex.
Main Methods:
- Co-immunoprecipitation assays to detect protein interactions.
- Western blotting to assess protein acetylation and degradation.
- Enzyme assays to measure MMR activity.
- Treatment with Trichostatin A (a histone deacetylase inhibitor) and CBP overexpression.
Main Results:
- CBP interacts with and acetylates MLH1, stabilizing it against proteasomal degradation.
- Acetylation, induced by Trichostatin A, promotes the assembly of MutSα and MutLα complexes.
- Overexpression of CBP enhances cellular MMR activity.
Conclusions:
- CBP plays a novel role in stabilizing MLH1, thereby enhancing the formation of the MutSα-MutLα complex.
- Increased MLH1 stability and complex formation by CBP lead to elevated cellular MMR activity.
- CBP is a key regulator of DNA mismatch repair, contributing to genomic stability.
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