Mlh1-KO Mouse

MLH1, Mut L homolog-1, is a key DNA mismatch repair protein. It participates in maintaining genome stability by rectifying errors that occur during DNA replication. Defects in MLH1-related DNA mismatch repair pathway can lead to microsatellite instability, which is associated with an increased risk of various cancers [2,3,4,7].

MLH1 deficiency has been linked to different cancers. In a case of Lynch syndrome, a patient with multiple cancers (colorectal, vulvar, facial, and endometrial) had MLH1/PMS2-deficient tumors, and a germline monoallelic constitutional epimutation of the MLH1 promoter was identified, highlighting a rare cause of Lynch syndrome [1]. In colorectal carcinoma, MLH1 proficient cells were less sensitive to 5-Fluorouracil-induced cytotoxic effect as MLH1 facilitated nucleophagy through interaction with LC3, showing its role in chemoresistance [2]. Also, MLH1 promoter hypermethylation was found in some Lynch syndrome-related cancers, indicating it may not be just a sporadic cancer mechanism [3]. In HCT116 cells, expressing MLH1 increased cellular resistance to radiation by activating PRKAC [4]. In Thailand, the MLH1 rs1800734 polymorphism variant AA was associated with an increased risk of colorectal cancer [5]. The ubiquitin ligase UBR4 and deubiquitylase USP5 were identified to oppositely modulate MLH1 stability, which is critical for DNA mismatch repair related diseases [6].

In conclusion, MLH1 is crucial for DNA mismatch repair and genome maintenance. Its dysregulation, whether through genetic mutations, epimutations, or protein stability changes, is associated with cancer development, especially colorectal and endometrial cancers. Studies on MLH1 contribute to understanding cancer mechanisms and may aid in developing better cancer screening, genetic counseling, and treatment strategies.

References:

1. Zyla, Roman, Graham, Tracy, Aronson, Melyssa, Mrkonjic, Miralem, Turashvili, Gulisa. 2021. MLH1 epimutation is a rare mechanism for Lynch syndrome: A case report and review of the literature. In Genes, chromosomes & cancer, 60, 635-639. doi:10.1002/gcc.22957. https://pubmed.ncbi.nlm.nih.gov/33934415/

2. Manzoor, Shaista, Saber-Ayad, Maha, Maghazachi, Azzam A, Hamid, Qutayba, Muhammad, Jibran Sualeh. 2021. MLH1 mediates cytoprotective nucleophagy to resist 5-Fluorouracil-induced cell death in colorectal carcinoma. In Neoplasia (New York, N.Y.), 24, 76-85. doi:10.1016/j.neo.2021.12.003. https://pubmed.ncbi.nlm.nih.gov/34952246/

3. Carnevali, Ileana Wanda, Cini, Giulia, Libera, Laura, Sessa, Fausto, Tibiletti, Maria Grazia. 2023. MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis. In Genes, 14, . doi:10.3390/genes14112060. https://pubmed.ncbi.nlm.nih.gov/38003003/

4. Huang, Yuling, Feng, Liu, Bao, Yongqiang, Li, Jingao, Jiang, Chunling. 2021. Expressing MLH1 in HCT116 cells increases cellular resistance to radiation by activating the PRKAC. In Experimental biology and medicine (Maywood, N.J.), 247, 426-432. doi:10.1177/15353702211059829. https://pubmed.ncbi.nlm.nih.gov/34787019/

5. Pongsavee, Malinee, Wisuwan, Kamol, Pongsavee, Kritpipat. 2023. MLH1 rs1800734 Pathogenic Variant among Patients with Colorectal Cancer in the Lower Northeastern Region of Thailand. In Asian Pacific journal of cancer prevention : APJCP, 24, 2911-2916. doi:10.31557/APJCP.2023.24.8.2911. https://pubmed.ncbi.nlm.nih.gov/37642081/

6. Mao, Chenyu, Li, Siqi, Che, Jun, Mao, Xinliang, Rao, Hai. 2024. The ubiquitin ligase UBR4 and the deubiquitylase USP5 modulate the stability of DNA mismatch repair protein MLH1. In The Journal of biological chemistry, 300, 107592. doi:10.1016/j.jbc.2024.107592. https://pubmed.ncbi.nlm.nih.gov/39032648/

7. Hitchins, M P, Ward, R L. 2009. Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. In Journal of medical genetics, 46, 793-802. doi:10.1136/jmg.2009.068122. https://pubmed.ncbi.nlm.nih.gov/19564652/