DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''MLH1''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
located on
chromosome 3. The gene is commonly associated with
hereditary nonpolyposis colorectal cancer.
Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
''.
Function
Variants in this gene can cause
hereditary nonpolyposis colon cancer (Lynch syndrome). It is a human
homolog of the ''E. coli'' DNA mismatch repair gene, mutL, which mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal. Defects in MLH1 are associated with the
microsatellite instability observed in hereditary nonpolyposis colon cancer. Alternatively spliced transcript variants encoding different isoforms have been described, but their full-length natures have not been determined.
Role in DNA mismatch repair
MLH1 protein is one component of a system of seven
DNA mismatch repair proteins that work coordinately in sequential steps to initiate repair of
DNA mismatches in humans.
Defects in mismatch repair, found in about 13% of colorectal cancers, are much more frequently due to deficiency of MLH1 than deficiencies of other DNA mismatch repair proteins.
The seven DNA mismatch repair proteins in humans are MLH1,
MLH3,
MSH2,
MSH3,
MSH6,
PMS1 and
PMS2.
In addition, there are
Exo1-dependent and Exo1-independent DNA mismatch repair subpathways.
DNA mismatches occur where one base is improperly paired with another base, or where there is a short addition or deletion in one strand of DNA that is not matched in the other strand. Mismatches commonly occur as a result of DNA replication errors or during genetic recombination. Recognizing those mismatches and repairing them is important for cells because failure to do so results in microsatellite instability] and an elevated spontaneous
mutation rate
In genetics, the mutation rate is the frequency of new mutations in a single gene, nucleotide sequence, or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mu ...
(mutator phenotype). Among 20 cancers evaluated,
microsatellite instable colon cancer (mismatch repair deficient) had the second highest frequency of mutations (after melanoma).
A heterodimer between MSH2 and MSH6 first recognizes the mismatch, although a heterodimer between MSH2 and MSH3 also can start the process. The formation of the MSH2-MSH6 heterodimer accommodates a second heterodimer of MLH1 and PMS2, although a heterodimer between MLH1 and either PMS3 or MLH3 can substitute for PMS2. This protein complex formed between the 2 sets of heterodimers enables initiation of repair of the mismatch defect.
Other gene products involved in mismatch repair (subsequent to initiation by DNA mismatch repair genes) include
DNA polymerase delta,
PCNA
Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase delta, DNA polymerase δ in eukaryotic cell (biology), cells and is essential for replication. PCNA is a homotrimer and achieves its ...
,
RPA,
HMGB1,
RFC and
DNA ligase I, plus
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...
and
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
modifying factors.
Deficient expression in cancer
Epigenetic repression
Only a minority of sporadic cancers with a DNA repair deficiency have a mutation in a DNA repair gene. However, a majority of sporadic cancers with a DNA repair deficiency do have one or more
epigenetic alterations that reduce or silence DNA repair gene expression.
In the table above, the majority of deficiencies of MLH1 were due to methylation of the promoter region of the ''MLH1'' gene. Another epigenetic mechanism reducing MLH1 expression is over-expression of
miR-155.
MiR-155 targets MLH1 and MSH2 and an inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer.
Deficiency in field defects
A
field defect is an area or "field" of epithelium that has been preconditioned by epigenetic changes and/or mutations so as to predispose it towards development of cancer. As pointed out by Rubin, "The vast majority of studies in cancer research has been done on well-defined tumors ''in vivo,'' or on discrete neoplastic foci ''in vitro.''
Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion."
Similarly, Vogelstein et al.
point out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells.
In the Table above, MLH1 deficiencies were noted in the field defects (histologically normal tissues) surrounding most of the cancers. If MLH1 is epigenetically reduced or silenced, it would not likely confer a selective advantage upon a stem cell. However, reduced or absent expression of MLH1 would cause increased rates of mutation, and one or more of the mutated genes may provide the cell with a selective advantage. The expression-deficient ''MLH1'' gene could then be carried along as a selectively neutral or only slightly deleterious passenger (hitch-hiker) gene when the mutated stem cell generates an expanded clone. The continued presence of a clone with an epigenetically repressed ''MLH1'' would continue to generate further mutations, some of which could produce a tumor.
Repression in coordination with other DNA repair genes
In a cancer, multiple DNA repair genes are often found to be simultaneously repressed.
In one example, involving ''MLH1'', Jiang et al.
conducted a study where they evaluated the mRNA expression of 27 DNA repair genes in 40
astrocytomas compared to normal brain tissues from non-astrocytoma individuals. Among the 27 DNA repair genes evaluated, 13 DNA repair genes, ''MLH1'', ''
MLH3'', ''
MGMT
MGMT () is an American rock band formed in 2002 in Middletown, Connecticut. It was founded by singers and multi-instrumentalists Andrew VanWyngarden and Benjamin Goldwasser, Ben Goldwasser.
Originally signed to Cantora Records by the nascent ...
,'' ''
NTHL1,'' ''
OGG1,'' ''
SMUG1,'' ''
ERCC1,'' ''
ERCC2'', ''
ERCC3'', ''
ERCC4'', ''
RAD50
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the ''RAD50'' gene.
Function
The protein encoded by this gene is highly similar to ''Saccharomyces cerevisiae'' Rad50, a protein involved in DNA double- ...
'', ''
XRCC4
DNA repair protein XRCC4 (hXRCC4) also known as X-ray repair cross-complementing protein 4 is a protein that in humans is encoded by the ''XRCC4'' gene. ''XRCC4'' is also expressed in many other animals, fungi and plants. hXRCC4 is one of severa ...
'' and ''
XRCC5'' were all significantly down-regulated in all three grades (II, III and IV) of astrocytomas. The repression of these 13 genes in lower grade as well as in higher grade astrocytomas suggested that they may be important in early as well as in later stages of astrocytoma. In another example, Kitajima et al.
found that immunoreactivity for MLH1 and
MGMT
MGMT () is an American rock band formed in 2002 in Middletown, Connecticut. It was founded by singers and multi-instrumentalists Andrew VanWyngarden and Benjamin Goldwasser, Ben Goldwasser.
Originally signed to Cantora Records by the nascent ...
expression was closely correlated in 135 specimens of gastric cancer and loss of MLH1 and MGMTappeared to be synchronously accelerated during tumor progression.
Deficient expression of multiple DNA repair genes are often found in cancers,
and may contribute to the thousands of mutations usually found in cancers (see
Mutation frequencies in cancers).
Meiosis
In addition to its role in DNA mismatch repair, MLH1 protein is also involved in
meiotic crossing over.
MLH1 forms a heterodimer with
MLH3 that appears to be necessary for
oocyte
An oocyte (, oöcyte, or ovocyte) is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ger ...
s to progress through metaphase II of
meiosis
Meiosis () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one c ...
.
Female and male ''MLH1''(-/-) mutant mice are infertile, and sterility is associated with a reduced level of
chiasmata.
During
spermatogenesis
Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the Mitosis, mitotic division of the stem cells located close to the basement membrane of ...
in ''MLH1''(-/-) mutant mice chromosomes often separate prematurely and there is frequent arrest in the first division of meiosis.
In humans, a common variant of the ''MLH1'' gene is associated with increased risk of sperm damage and male infertility.

MLH1 protein appears to localize to sites of crossing over in meiotic chromosomes.
Recombination during meiosis is often initiated by a DNA double-strand break (DSB) as illustrated in the accompanying diagram. During recombination, sections of DNA at the 5' ends of the break are cut away in a process called ''resection''. In the ''strand invasion'' step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a
displacement loop (
D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see
Genetic recombination
Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryot ...
). The pathway leading to a CO involves a double
Holliday junction (DHJ) intermediate. Holliday junctions need to be resolved for CO recombination to be completed.
In the budding yeast ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
'', as in the mouse, MLH1 forms a heterodimer with MLH3. Meiotic CO requires resolution of
Holliday junctions through actions of the MLH1-MLH3
heterodimer. The MLH1-MLH3
heterodimer is an
endonuclease
In molecular biology, endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain (namely DNA or RNA). Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (with regard to sequence), while man ...
that makes single-strand breaks in
supercoiled double-stranded DNA.
MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during
meiosis
Meiosis () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one c ...
.
MLH1-MLH3 heterodimer (MutL gamma) together with
EXO1 and
Sgs1 (ortholog of
Bloom syndrome helicase) define a joint molecule resolution pathway that produces the majority of crossovers in budding yeast and, by inference, in mammals.
Clinical significance
It can also be associated with
Turcot syndrome.
Interactions
MLH1 has been shown to
interact with:
*
Bloom syndrome protein
*
Exonuclease 1,
*
MBD4,
*
MSH4
MutS protein homolog 4 is a protein that in humans is encoded by the ''MSH4'' gene.
Function
The MSH4 and MSH5 proteins form a hetero-oligomeric structure (heterodimer) in yeast and humans. In the yeast ''Saccharomyces cerevisiae'' MSH4 and M ...
,
*
Myc,
[ and
* PMS2.]
See also
* Mismatch repair#MutH: an endonuclease present in E. coli and Salmonella
References
Further reading
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External links
Information on HNPCC
from the National Institute of Health
The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Servic ...
GeneReviews/NCBI/NIH/UW entry on Lynch syndrome
*
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{{DNA repair
DNA repair
Mutation
Oncogenes