Within our cells, the proteins MutS and MutL act as guardians of our genetic blueprint. They are part of a surveillance system that scans DNA, the molecule carrying all our genetic instructions. Their primary function is to identify and initiate the repair of errors that occur when DNA is copied. This process helps prevent the accumulation of errors that could otherwise disrupt normal cellular function, ensuring the stable transfer of genetic material between cell generations.
The DNA Mismatch Repair Pathway
Deoxyribonucleic acid (DNA) holds the instructions for building and operating an organism. When a cell divides, it makes a copy of its DNA in a process called replication. While highly accurate, this process can introduce errors like incorrect base pairings or small insertions and deletions, known as DNA mismatches.
To correct these mistakes, cells use a defense mechanism called the DNA Mismatch Repair (MMR) system. This pathway detects and corrects mismatches that escape the initial proofreading functions of replication machinery. The MMR system maintains genomic stability by reversing these errors, which significantly reduces the rate of spontaneous mutations. MutS and MutL are the proteins that initiate this repair cascade.
How MutS and MutL Collaborate in Repair
The DNA Mismatch Repair pathway is initiated by the coordinated actions of MutS and MutL. The process begins when the MutS protein, acting as a homodimer, scans newly synthesized DNA and binds directly to the site of a mismatch. This binding event causes a change in the shape of the MutS protein, which signals that an error has been found.
Once MutS is bound to the mismatched DNA, it recruits the MutL protein. MutL then binds to the MutS-DNA complex, forming a larger assembly that coordinates the subsequent steps of repair. The MutS-MutL complex interacts with other enzymes to cut the flawed DNA strand and unwind it, allowing for the removal of the erroneous segment. Finally, a DNA polymerase synthesizes a new, correct strand, and a ligase seals the gap.
Human Homologs MSH and MLH
The process of mismatch repair is highly conserved across species. While bacteria have MutS and MutL proteins, humans and other eukaryotes have functionally equivalent proteins known as homologs. The human counterparts to MutS are called MSH (MutS homolog) proteins, and the equivalents to MutL are the MLH (MutL homolog) proteins.
In humans, these proteins work in pairs to form complexes. The main MSH proteins include MSH2, MSH3, and MSH6, which combine to form complexes like MutSα (MSH2/MSH6) and MutSβ (MSH2/MSH3) that recognize different types of mismatches. Similarly, the MLH protein family includes MLH1 and PMS2, which form the MutLα complex that is central to the repair process.
Impact of Defective MutS/MutL (and MSH/MLH) Function
When MSH and MLH proteins are defective, the MMR system is unable to correct replication errors. This leads to an increased rate of spontaneous mutations throughout the genome, a condition referred to as a “mutator phenotype.” Cells with a defective MMR pathway often exhibit genetic instability known as microsatellite instability (MSI), where short, repetitive DNA sequences frequently expand or contract.
This accumulation of mutations can disrupt genes that regulate cell growth, which increases the risk of developing cancer. The most well-known condition from inherited defects in MMR genes is Lynch syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Lynch syndrome results from inherited mutations in genes such as:
- MSH2
- MLH1
- MSH6
- PMS2
Individuals with this syndrome have a higher lifetime risk of developing colorectal cancer, endometrial cancer, and various other cancers.