MLH1 gene
The MLH1 gene, also known as human MutL homolog 1, plays a critical role in the DNA mismatch repair (DMMR) system, which is essential for maintaining genomic stability. This gene encodes a protein that collaborates with other proteins to identify and correct errors that occur during DNA replication, specifically mismatches created when incorrect nucleotides are incorporated. If these mismatches are not corrected, they can lead to permanent mutations, contributing to various forms of cancer.
The activity of MLH1 is regulated by its interactions with proteins like PMS2, MSH2, and MSH6, forming complexes that detect mismatches and initiate the repair process. However, mutations in the MLH1 gene or its promoter can lead to a loss of function, resulting in microsatellite instability (MSI), a condition associated with various cancers, particularly Lynch syndrome, which increases the risk of colorectal and endometrial cancers. Additionally, MLH1 insufficiency can complicate cancer treatment, as it can impair the ability of cells to respond to DNA damage. Understanding the role of MLH1 is vital in the context of cancer genetics, as it highlights the intricate relationship between DNA repair mechanisms and cancer susceptibility.
MLH1 gene
ALSO KNOWN AS: MutL homolog; human MutL homolog 1
SIGNIFICANCE: The protein encoded by MLH1, or human MutL homolog 1 gene, is an important member of the DNA mismatch repair (DMMR) system. Mismatches occur during DNA replication when protein machinery responsible for copying strands of DNA places the incorrect nucleotide in a new DNA strand. Uncorrected mismatches lead to permanent mutations. MLH1 functions in correcting mismatches.
MLH1 Activity and Regulation
The recognition of DNA mismatches requires MLH1, which functions in a complex that includes three other proteins. MLH1 binds with PMS2 (postmeiotic segregation 2), PMS1, or MLH3. This pair of proteins binds with another pair of proteins responsible for sensing mismatches. This pair consists of MSH2 and MSH6 or MSH2 and MSH3. The identity of the MutS heterodimer that binds to the site of the mismatch is dependent on the size of the defect. After the MutS heterodimer recognizes the mismatch, the MLH1 heterodimer binds to the MutS heterodimer and recruits other proteins in the DMMR pathway. The MLH1-PMS2 heterodimer has been identified as an endonuclease, the activity of which is also dependent on and several other proteins. Endonucleases cut the bonds between nucleotides.
The expression of MLH1, as with other genes, is dependent not only on the sequence of the gene but also on the state of its promoter. A gene promoter is typically located just before the start of the gene, is CpG-rich (cytosine-phosphate-guanine), and allows for the gene to be switched on or off. Though several hundred mutations in the MLH1 gene have been described in humans in association with cancer, most eliminations of MLH1 are dependent on increased methylation of the promoter. Mutations in the sequence of MLH1 often lead to the absence of or a shortened version of the protein.
MLH1, Microsatellite Instability, and the Methylator Phenotype
In cells with a MLH1 insufficiency, mutations accumulate in the genome from an inactivated DMMR pathway. Regions of nucleotide repeats are especially susceptible to accumulation of mutations. Microsatellites are regions of DNA consisting of short repeats of nucleotides, such as a repeating A or CAG. When DMMR is inactivated, strand slippages, which often occur during copying of DNA, are not corrected. Where microsatellites are located in coding regions of genes, resulting mutations can produce an altered amino acid sequence or shortened protein product of that gene, though longer proteins are possible. The altered or shortened protein frequently has no function.
Other genes have also been observed inactivated due to increased methylation, a form of epigenetic control, at their promoters in individuals with a MLH1 insufficiency. This effect is referred to as the methylator phenotype and is thought to be responsible for decreased expression of these genes and increased disregulation of cells.
MLH1 and Cancer
Inactivation of the DMMR and DNA damage response (DDR) pathways can lead to mutations in genes controlling cell growth and development as well as programmed cell death, also called apoptosis. When this occurs, normal cells can become cancerous. Mutations in MLH1 and other genes cannot only lead to cancer, but can make certain types of cancer cells more difficult to treat. Many chemotherapies work by causing further damage to DNA. MLH1 insufficiency can cause inactivation of genes that would normally detect this damage and induce apoptosis in cancer cells.
Microsatellite-instable (MSI) cancers are assessed by variation in length at a set of five microsatellites selected by the National Cancer Institute. Low instability (MSI-L) is defined by instability at one of five markers. High instability (MSI-H) is defined by instability at two or more markers. Extensive methylation of the MLH1 promoter has been associated with MSI-H in recent studies.
Impact
MLH1 insufficiency is associated with an increased risk of cancers that can be linked in a family through a MLH1 defect in a condition called Lynch syndrome, including human nonpolyposis colorectal cancer (HNPCC) and endometrial (uterine) cancer. Other cancers, such as ovarian, stomach, small intestine, and pancreatic cancers, have also been linked to MLH1 insufficiency, though early studies located HNPCC and MLH1 in the same region of the genome. In humans, the MLH1 gene is located on the short arm of chromosome 3 at p21.3. The DMMR system does not recognize and correct all mismatches equally well. C-C mismatches are most poorly recognized and corrected by the DMMR pathway.
Key terms
- epigeneticalteration in gene function that is independent of the gene’s DNA sequence
- heterodimertwo different proteins which are bound to each other to perform a single function neither could perform alone
- methylatedwhen a methyl (–CH3) group is attached to a molecule, such as a nucleotide
- microsatellite instability (MSI)errors in short repeat tracks, typically repeats of 1-3 nucleotides, often associated with loss of DMMR
- promoterregion of gene that binds factors necessary to initiate transcription of DNA into RNA
Bibliography
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Allis, C. David, Thomas Jenuwein, Danny Reinberg, and Marie-Laure Caparros. Epigenetics. Woodbury: Cold Spring Harbor Laboratory P, 2007. Print.
Casea, Ashley S., et al. “Clustering of Lynch Syndrome Malignancies with No Evidence for a Role of DNA Mismatch Repair.” Gynecologic Oncology 108.2 (2008): 438–44. Print.
Kosinski, Jan, Inga Hinrichsen, Janusz M. Bujnicki, Peter Friedhoff, and Guido Plotz. “Identification of Lynch Syndrome Mutations in the MLH1-PMS2 Interface That Disturb Dimerization and Mismatch Repair.” Human Mutation 31.8 (2010): 975–82. Print.
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“MLH1.” Medline Plus, 1 Apr. 2020, medlineplus.gov/genetics/gene/mlh1/. Accessed 9 Sept. 2024.
Ward, Robyn L., Timothy Dobbins, Noralane M. Lindor, Robert W. Rapkins, and Megan P. Hitchins. “Identification of Constitutional MLH1 Epimutations and Promoter Variants in Colorectal Cancer Patients from the Colon Cancer Family Registry.” Genetics in Medicine 15.1 (2012): 25–35. Print.