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@ARTICLE{Wolf:602295,
      author       = {Wolf, Karla and Kosinski, Jan and Gibson, Toby J and Wesch,
                      Nicole and Dötsch, Volker and Genuardi, Maurizio and
                      Cordisco, Emanuela Lucci and Zeuzem, Stefan and Brieger,
                      Angela and Plotz, Guido},
      title        = {{A} conserved motif in the disordered linker of human
                      {MLH}1 is vital for {DNA} mismatch repair and its function
                      is diminished by a cancer family mutation},
      journal      = {Nucleic acids symposium series},
      volume       = {51},
      number       = {12},
      issn         = {0305-1048},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {PUBDB-2024-00570},
      pages        = {6307 - 6320},
      year         = {2023},
      note         = {ISSN 1362-4962 not unique: **2 hits**. Deutsche
                      Forschungsgemeinschaft (DFG) [PL688 2/1 toG.P.]. Funding for
                      open access charge: Institutional budget.},
      abstract     = {DNA mismatch repair (MMR) is essential for correction of
                      DNA replication errors. Germline mutations of the human MMR
                      gene MLH1 are the major cause of Lynch syndrome, a heritable
                      cancer predisposition. In the MLH1 protein, a non-conserved,
                      intrinsically disordered region connects two conserved,
                      catalytically active structured domains of MLH1. This region
                      has as yet been regarded as a flexible spacer, and missense
                      alterations in this region have been considered
                      non-pathogenic. However, we have identified and investigated
                      a small motif (ConMot) in this linker which is conserved in
                      eukaryotes. Deletion of the ConMot or scrambling of the
                      motif abolished mismatch repair activity. A mutation from a
                      cancer family within the motif (p.Arg385Pro) also
                      inactivated MMR, suggesting that ConMot alterations can be
                      causative for Lynch syndrome. Intriguingly, the mismatch
                      repair defect of the ConMot variants could be restored by
                      addition of a ConMot peptide containing the deleted
                      sequence. This is the first instance of a DNA mismatch
                      repair defect conferred by a mutation that can be overcome
                      by addition of a small molecule. Based on the experimental
                      data and AlphaFold2 predictions, we suggest that the ConMot
                      may bind close to the C-terminal MLH1-PMS2 endonuclease and
                      modulate its activation during the MMR process.},
      cin          = {CSSB-EMBL-JK},
      ddc          = {540},
      cid          = {I:(DE-H253)CSSB-EMBL-JK-20210701},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      experiment   = {EXP:(DE-MLZ)NOSPEC-20140101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37224528},
      UT           = {WOS:000992467000001},
      doi          = {10.1093/nar/gkad418},
      url          = {https://bib-pubdb1.desy.de/record/602295},
}