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Scientific result | Structural biology | Cancer
Lynch syndrome is a genetic, hereditary ailment that predisposes a
person to colorectal cancer. It is thought that three genes, MLH1, MSH2 and
MSH6, are primarily responsible and that these genes regulate errors that occur
during DNA replication, especially during cellular division.Researchers targeted
the protein corresponding to MLH1, one of the central proteins involved in the
DNA repair pathway (termed the “mismatch repair pathway” because it repairs
errors related to DNA replication). They used X-ray crystallography to
understand how it functions and detected exactly where the mutations occur. The
technique consists of crystallizing a protein and studying how the crystal
refracts an X-ray beam, in much the same way as a prism refracts sunlight. Since
the angle of deviation is related to the distance between atoms, crystallography
provides the atomic structure of the protein. Rather obvious in this summary, in
this case the method required twelve years of work from creation of the first
crystals to the final “image”. Illustration of the atomic structure of MLH1
structure (light and dark green) used to locate the mutations identified on a
panel of patients. This image shows a classification of mutations: very
severe (red), moderately severe (cyan) or whose severity if difficult to predict
according to the image (gray). Illustration credit: CEA/CNRS/Université
Paris-Sud.In addition to its contribution to basic research, this article is the
starting point of a clinical diagnostic support project. Numerous mutations
identified on MLH1 do not directly explain the syndrome. Their involvement can
only be established by integrating various clinical, tumoral and familial
Researchers and clinicians are working on a list of 70 MLH1 mutations
observed in a patient panel. With results from Saclay, researchers have already
pinpointed the potential impact of each mutation on the DNA mismatch repair
pathway. Conducted by the Marseille public hospital system and Institut Curie,
the objective of this project is to use functional data to personalize
treatment for patients who carry these mutations, in combination with other
factors. The impact of these mutations can be divided into three categories: 1.
Very severe (harmful mutation, protein deployed) ; 2. Moderately severe (protein
cannot interact with its environment); 3. Not pronounced. After sequencing the
genome of persons at risk (since the syndrome is hereditary), doctors may then
have a classification system at their disposal to help them determine preventive
treatment for colorectal cancer .
Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.