The basic MMR machinery involves two families of proteins MutS and MutL
convoluted to form heterodimers in contrast to bacteria, which function as homodimers.
D, Cancer heterogeneity for MLH1 (MutL
homolog 1) expression in a high- grade colorectal adenocarcinoma showing a positive immunoreaction in the mucoid, differentiated portion (upper left, above the dotted line, which separates the 2 components) and a negative immunoreaction in the other neoplastic cells, marked by a solid-type growth pattern.
Germline testing for germline mutations in the MMR genes--mutS homologue 2 (MSH2), mutL
homologue (MLH1), mutS homologue 6 (MSH6), and postmeiotic segregation increased 2 (PMS2)--can discriminate Lynch syndrome from Lynch kindreds.
It is testified that some major genes are actually involved in the malignant transformation of ovarian endometriosis; among these contributing genes, epigenetic inactivation of Runt-related transcription factor 3 (RUNX3) , human mutL
homolog 1 (hMLH1) , E-cadherin (CDH1) , Ras-association domain family of gene 2 (RASSF2) , and P16 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN)  by promoter hypermethylation was well observed; however, long interspersed nuclear element-1 (LINE-1)  and syncytin-1  were hypo-methylated and activated.
The distribution of the DNA mismatch repair (MMR) proteins, that is, MutL
homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), and PMS1 homolog 2 (PMS2), in the different entities might in addition also be of differential diagnostic and pathogenetic interest.
Homolog 1 (MLH1), a member of MMR genes, has been suggested to be associated with both hereditary and sporadic CRCs through either genetic polymorphisms or epigenetic regulations (Richter et al.
Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL
homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred m utations in the resistant group were associated with the resistance of targeted therapy.
Among these genes, 9 [aprataxin (APTX), aprataxin and PNKP like factor (APLF), X-ray repair cross complementing 4 (XRCC4), BRCA1 interacting protein C-terminal helicase 1 (BRIP1), Fanconi anemia complementation group B (FANCB), Fanconi anemia complementation group M (FANCM), damage specific DNA binding protein 2 (DDB2), XPC complex subunit, DNA damage recognition and repair factor (XPC), and mutL
homolog 3 (MLH3)] were over-expressed in CTC-MCC-41 cells and only 4 [DNA polymerase mu (POLM), RAD51 recombinase (RAD51), ERCC excision repair 1 (ERCC1), and tumor protein p53 binding protein 1 (TP53BP1)] in HT-29 cells.
The mismatch repair system was first studied in bacteria in which three proteins, MutS, MutL
, and MutH, were identified.
Sabates-Bellver et al., "Expression of the MutL
homologue hMLH3 in human cells and its role in DNA mismatch repair," Cancer Research, vol.
Recognition of single base replication errors is performed by the MutS[alpha] (MSH2-MSH6 heteroduplex) or MutS[beta] (MSH2-MSH3 heteroduplex), excision of the lagging strand from the mismatch by one of the MutL
complexes (mainly MutL[alpha] formed by MLH1/PMS2) recruited by MutS protein, and resynthesis of the excised-DNA and ligation by DNA polymerase delta and DNA ligase I .