2. Academic Validation
  3. The ubiquitin ligase UBR4 and the deubiquitylase USP5 modulate the stability of DNA mismatch repair protein MLH1

The ubiquitin ligase UBR4 and the deubiquitylase USP5 modulate the stability of DNA mismatch repair protein MLH1

  • J Biol Chem. 2024 Jul 18;300(8):107592. doi: 10.1016/j.jbc.2024.107592.
Chenyu Mao 1,  Siqi Li 1,  Jun Che 1,  Dongzhou Liu 2,  Xinliang Mao 3,  Hai Rao 4
Affiliations

Affiliations

  • 1 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 2 Department of Rheumatology and Immunology, Shenzhen People's Hospital, Shenzhen, Guangdong, China; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China.
  • 3 Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China. Electronic address: xinliangmao@gzhmu.edu.cn.
  • 4 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China; Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China. Electronic address: raoh@sustech.edu.cn.
PMID: 39032648 DOI: 10.1016/j.jbc.2024.107592
Abstract

MLH1 plays a critical role in DNA mismatch repair and genome maintenance. MLH1 deficiency promotes Cancer development and progression, but the mechanism underlying MLH1 regulation remains enigmatic. In this study, we demonstrated that MLH1 protein is degraded by the ubiquitin-proteasome system and have identified vital cis-elements and trans-factors involved in MLH1 turnover. We found that the region encompassing the Amino acids 516 to 650 is crucial for MLH1 degradation. The mismatch repair protein PMS2 may shield MLH1 from degradation as it binds to the MLH1 segment key to its turnover. Furthermore, we have identified the E3 ubiquitin Ligase UBR4 and the deubiquitylase USP5, which oppositely modulate MLH1 stability. In consistence, UBR4 or USP5 deficiency affects the cellular response to nucleotide analog 6-TG, supporting their roles in regulating mismatch repair. Our study has revealed important insights into the regulatory mechanisms underlying MLH1 proteolysis, critical to DNA mismatch repair related diseases.

Keywords

DNA mismatch repair; E3 ligase; MLH1; deubiquitylase; ubiquitin.

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