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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11375253 | PMC |
| http://dx.doi.org/10.1016/j.jbc.2024.107592 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
[NTRK gene fusion and molecular pathological characteristics of mismatch repair deficient colorectal cancer].
Zhonghua Bing Li Xue Za Zhi
February 2025
Department of Pathology, People's Hospital of Zhengzhou University/People's Hospital of Henan University, Zhengzhou 450043, China.
To investigate the expression pattern of pan-TRK protein in colorectal cancers with NTRK gene fusion and mismatch repair deficient (dMMR) and to analyze its molecular pathological characteristics. A total of 117 dMMR colorectal cancers diagnosed in the Department of Pathology of Henan Provincial People's Hospital, Zhengzhou, China from 2020 to 2023 were collected. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and DNA/RNA-based next-generation sequencing (NGS) were used to detect pan-TRK protein expression and fusion partner genes in tumors, and to further explore the correlation between pan-TRK staining patterns and partner genes.
View Article and Find Full Text PDF[Application of PMS2 and MSH6 double-antibody detection in screening of mismatch repair deficient tumors].
Zhonghua Bing Li Xue Za Zhi
February 2025
Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
To investigate whether the immunohistochemical results of two markers PMS2 and MSH6 (2-MMR) could replace the four markers MLH1, PMS2, MSH2 and MSH6 (4-MMR) to detect mismatch repair deficient (dMMR) cancers. A retrospective analysis was conducted with summary of immunohistochemical data from 7 867 cases of gastric cancer, colorectal cancer, endometrial cancer, and other diseases in the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China, from March 2018 to March 2023. The consistency of 2-MMR and 4-MMR results was examined.
View Article and Find Full Text PDFPD-1 and PD-L1 Expression in Endometrial Cancer: A Systematic Review of the Literature.
J Clin Med
January 2025
Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35122 Padua, Italy.
Cancer immunotherapy through the use of PD-1/PD-L1 inhibitors have shown significant promise in endometrial carcinoma (EC), particularly in tumors with microsatellite instability (MSI) or mismatch repair deficiency (dMMR), present in approximately 30% of cases. This review evaluated PD-L1 and PD-1 expression as potential biomarkers for immunotherapy response in EC, focusing on their relationship with MSI status. A systematic review, adhering to PRISMA guidelines, analyzed studies from MEDLINE and Embase until February 2023 on PD-1/PD-L1 expression in EC stratified by MSI status, including diverse study designs but excluding conference abstracts, with independent screening, data extraction, and additional reference checks to ensure comprehensive coverage.
View Article and Find Full Text PDFLynch Syndrome-Impact of the Type of Deficient Mismatch Repair Gene Mutation on Diagnosis, Clinical Presentation, Surveillance and Therapeutic Approaches.
Medicina (Kaunas)
January 2025
Department of Surgery, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania.
In today's world, with its continuing advancements in genetics, the identification of Lynch syndrome (LS) increasingly relies on sophisticated genetic testing techniques. Most guidelines recommend a tailored surveillance program, as well as personalized prophylactic and therapeutic approaches, according to the type of dMMR gene mutation. Carriers of path_MLH1 and path_MSH2 genes have a higher risk of developing colorectal cancer (CRC), despite intensive colonoscopic surveillance.
View Article and Find Full Text PDFEffects of Microsatellite Instability on the Clinical and Pathological Characteristics of Colon Cancer and the Diagnostic Accuracy of Preoperative Abdominal CT Scans.
Diagnostics (Basel)
January 2025
Gastroenterology Surgery Department, Antalya Training and Research Hospital, Varlık, Kazım Karabekir Cd., Muratpaşa 07100, Antalya, Turkey.
: Microsatellite-stable (MSS) and microsatellite-instable (MSI) colon cancer (CC) cases have different characteristics. These characteristics may impact the accuracy of abdominal computed tomography (CT) scan examinations in MSI CC. : A retrospective analysis was conducted to examine the effects of MSI CC on patients' clinical and tumor characteristics.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!