MLH1
小结
MLH1是抑癌基因，编码蛋白参与DNA错配修复。MLH1蛋白对DNA错配修复途径至关重要，该途径是用于校正错配的核苷酸和插入/缺失环的细胞内机制，MLH1与PMS2（最常见），PMS1或MLH3以异二聚化形成切割受损链的内切核酸酶复合物，导致其局部切除。MLH1中的突变导致不能正确修复错配和插入/缺失环，其最常与微卫星重复序列相关。MLH1的胚系突变与Lynch综合征相关，并且可能通过肿瘤中的微卫星不稳定性导致基因组不稳定。具有MLH1失活突变的肿瘤可能表现出MSI-H。MLH1突变发生在多种肿瘤类型中，但最常见于散发性结肠癌，胃癌和子宫内膜癌的特定亚群，以及遗传性非息肉病性结肠癌（HNPCC）。
MLH1 encodes a tumor suppressor involved in DNA mismatch repair. Select mutations of MLH1 are associated with Lynch syndrome and can lead to genomic instability via microsatellite instability in tumors.The MLH1 protein is essential for DNA mismatch repair pathway. This pathway is an intracellular mechanism used to correct mismatched nucleotides and insertion/deletion loops that are erroneously incorporated into the newly synthesized strand of DNA during replication, using the parental strand of DNA as a template. As part of this pathway, MLH1 heterodimerizes with PMS2 (most commonly), PMS1 or MLH3 to form an endonuclease complex that incises the damaged strand, leading to its local excision. Mutations in MLH1 lead to an inability to correctly repair mismatches and insertion/deletion loops, which are most frequently associated with microsatellite repeat sequences. Alterations in microsatellite repeat sequences can be particularly deleterious with their potential to create frameshift mutations in a variety of other genes. Mutations in MLH1 occur in multiple tissue types, but are most common in a specific subset of sporadic colon, gastric and endometrial cancers, as well as the inherited lynch syndrome, sometimes referred to as hereditary non-polyposis colon cancer (HNPCC). MLH1 acts as a classic tumor suppressor gene, where loss of function of one allele due to an inherited or somatic mutation is eventually accompanied by the loss of function of the other allele through one of several mechanisms, such as mutation, loss of heterozygosity or epigenetic silencing. Clinically, mutational status of specific DNA mismatch repair genes is not frequently tested. However, a screening test for micro satellite instability (MSI) is commonly used to identify a non-specific defect of the mismatch repair system. Tumors with inactivating MLH1 mutations are likely to exhibit an MSI-high phenotype. Chemotherapy-induced DNA damage or inhibition of other DNA-repair/synthesis pathway genes has been shown in model systems to mediate synthetic lethality. Examples of this include increased sensitivity to a PARP-1 inhibitor in colorectal cancer cell lines with mutated MRE11, cytotoxicity of methotrexate and POLB/POLG inhibitors in MSH2- and MLH1-deficient cells, respectively. Indeed, defects in the MMR pathway have been associated with improved response to radio- and chemotherapy and immunotherapy . In specific regard to immunotherapy, the FDA approved pembrolizumab for all mismatch repair deficient (dMMR) and MSI tumors, irrespective of specific tumor etiology.