Mlh1-flox Mouse

MLH1, Mut L homolog-1, is a key DNA mismatch repair protein [4]. It participates in maintaining genome stability by rectifying errors during DNA replication, thus playing a crucial role in preventing cancer development. The ubiquitin-proteasome system is involved in regulating MLH1 protein degradation, with the E3 ubiquitin ligase UBR4 and deubiquitylase USP5 oppositely modulating its stability [6].

MLH1 deficiency is associated with various cancers. In Lynch syndrome, a rare mechanism can be a germline monoallelic constitutional epimutation of the MLH1 promoter, which can lead to multiple malignancies like colorectal, vulvar, and endometrial cancers [1]. In colorectal cancer, MLH1 proficient cells are less sensitive to 5-Fluorouracil-induced cytotoxic effect, as MLH1 mediates cytoprotective nucleophagy by interacting with the autophagy marker LC3 [2]. Also, MLH1 promoter methylation can be a "second hit" in Lynch syndrome carcinogenesis, and a polymorphism (rs1800734) in its core promoter region is associated with an increased risk of colorectal cancer in the lower northeastern region of Thailand [3,5].

In conclusion, MLH1 is essential for DNA mismatch repair and genome maintenance. Its deficiency is linked to cancer development, especially in Lynch syndrome and colorectal cancer. Studies on MLH1-related mechanisms, such as its role in drug-induced cell death and promoter methylation, contribute to understanding cancer carcinogenesis and may provide potential targets for cancer prevention and treatment.