PMS genes
PMS genes, specifically PMS1 and PMS2, play a critical role in the DNA mismatch repair (MMR) process, which is essential for correcting errors that occur during DNA replication. These genes help prevent the accumulation of mutations that could lead to cancer. PMS2, in particular, is associated with hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, where a mutation in one copy of PMS2 significantly increases cancer risk. Both PMS1 and PMS2 are involved in forming heterodimers with other MMR proteins to effectively identify and repair mismatched DNA bases. Additionally, PMS2 is implicated in responding to DNA damage from methylating agents, which are often used in cancer treatments. In cases where both copies of PMS2 are mutated, an individual may develop Turcot syndrome, which is characterized by early-onset cancers of the central nervous system and colorectal tumors. Understanding the functions and implications of PMS genes is vital for comprehending certain hereditary cancer syndromes and improving cancer treatment strategies.
Subject Terms
PMS genes
SIGNIFICANCE: PMS genes function in DNA mismatch repair, where they help correct errors that arise during replication. If these errors go uncorrected, mutations will accumulate in the genome, eventually leading to cancer. Deficiency in the PMS2 gene can cause hereditary nonpolyposis colon cancer as well as Turcot syndrome.
Genetics
There are two genes in the PMS family, PMS1 and PMS2. PMS stands for postmeiotic segregation, the name given to the yeast homologue due to its role in regulating during meiosis. In humans, PMS1 is located on chromosome 2q31-33, and PMS2 is located on 7p22.
MMR and Cancer
The main cellular role for the PMS genes is in mismatch repair. When cells divide, the DNA is replicated by enzymes called polymerases that use the existing strand as a copy for the new strand. The polymerases occasionally make an error, creating a mismatch between the template strand and the newly replicated strand. MMR functions to correct these errors before they become mutations. The PMS genes are part of the MutL heterodimer. PMS2 is in MutLalpha, where it binds MLH1. PMS1 also binds MLH1 as part of MutLbeta. The MutL heterodimer gets recruited to mismatched bases in the DNA by the MutS heterodimer, typically MutSalpha, which is composed of MSH2 and MSH6. Once bound to DNA, MutS and MutL recruit downstream factors that excise the newly replicated strand in the area of the mismatch and fill it in with the correct base. If MMR is compromised, then the mismatched bases will go uncorrected and become mutations in the next round of replication. An increased rate of mutation accumulation can eventually lead to cancer.
If a mismatch repair gene is defective, it causes hereditary nonpolyposis colon cancer, or Lynch syndrome. The majority of HNPCC cases are caused by mutations in either MLH1 or MSH2; less than 5 percent of HNPCC cases are due to inherited mutations in PMS2, and no HNPCC-causing mutations have been definitively attributed to PMS1. However, PMS2 has a number of pseudogenes that have made detecting mutations in PMS2 difficult. HNPCC is an autosomal dominant disorder; only one copy of PMS2 must be mutated to cause the disease. Eventually, the remaining copy of PMS2 is lost in a subset of cells. These cells have a high mutation rate, increasing the likelihood of activating genes that promote cancer as well as altering genes that prevent it.
In addition to its role in repairing errors, PMS2 also responds to damage caused by methylating agents. Methylating agents damage DNA by creating lesions that cannot be repaired by normal cellular repair mechanisms. The cells then signal in order to prevent the damaged cells from continuing to proliferate. PMS2 is necessary for cells to signal apoptosis in response to methylation. Cells deficient in PMS2 will continue to grow in the presence of methylating agents.
Turcot Syndrome
Turcot syndrome, also known as mismatch repair cancer syndrome, is caused by mutation in both alleles of a mismatch repair gene, including PMS2. It differs from HNPCC in that it causes early-onset malignancies of the central nervous system as well as colorectal tumors. Some of the cancers specifically associated with Turcot syndrome include colon cancer, astrocytoma, ependymoma, glioma, blioblastoma, medulloblastoma, and basal cell carcinoma. In addition, patients often present with light brown spots on the skin, termed café-au-lait spots, or noncancerous fatty spots called lipomas. Due to having mutations in both copies of PMS2, the severity of Turcot syndrome is increased compared to HNPCC, with cancers presenting much earlier.
Impact
The PMS genes are an essential component of mismatch repair, which is necessary to maintain genomic stability in the cell. Mutation in one copy of PMS2 can lead to HNPCC, while mutation in both copies can cause Turcot syndrome. Furthermore, PMS2 was the first MMR gene to be identified as causing Turcot syndrome. It was later shown that the other MMR genes could cause Turcot syndrome as well. PMS2 also responds to DNA damage caused by methylating agents, signaling cell death. Such methylating agents are often used in chemotherapeutic settings; for example, 6-mercaptopurine, which is used to treat childhood leukemias. Functioning MMR is necessary for these drugs to be effective. It has been demonstrated that tumors can become resistant to these drugs by mutating MMR.
Key terms
- apoptosisprogrammed cell death
- DNA mismatch repair (MMR)cellular mechanism for correcting mismatches in DNA that occur during replication; also suppresses aberrant recombination and signals cell death from chemical damage
- hereditary nonpolyposis colon cancer (HNPCC)also called Lynch syndrome; cancer caused by a deficiency in one copy of a mismatch repair gene; patients with HNPCC have an 80 percent lifetime risk of developing colorectal cancer and women with HNPCC have a 20 to 60 percent lifetime risk of developing endometrial cancer
- heterodimertwo different proteins binding together to form a complex
- methylation damagecertain chemicals, termed methylators, cause methyl (CH3) groups to incorporate into DNA; these lesions are toxic to cells
- Turcot syndromecancer syndrome defined by early onset hematological and CNS malignancies as well as colorectal cancer
Bibliography
Alberts, Bruce, et al. Molecular Biology of the Cell. New York: Garland, 2002. Print.
Hodgson, S. V., et al. A Practical Guide to Human Cancer Genetics. London: Springer, 2013. eBook Collection (EBSCOhost). Web. 7 Aug. 2014.
Kufe, Donald W., et al., eds. Cancer Medicine. Hamilton: BC Decker, 2003. Print.
Nussbaum, Robert L., Roderick McInnes, and Huntington F. Willard. Genetics in Medicine. 7th ed. New York: Saunders, 2007. Print.
Tomsic, J, et al. "Recurrent and Founder Mutations in the PMS2 Gene." Clinical Genetics 83.3 (2013): 238–43. Academic Search Elite. Web. 7 Aug. 2014.
"Turcot Syndrome." Cleveland Clinic, 24 Jan. 2022, my.clevelandclinic.org/health/diseases/22315-turcot-syndrome. Accessed 10 Sept. 2024.
Vogelsang, Matjaž. DNA Alterations in Lynch Syndrome: Advances in Molecular Diagnosis and Genetic Counseling. New York: Springer, 2013. Digital file.