A conserved motif in the disordered linker of human MLH1 is vital for DNA mismatch repair and its function is diminished by a cancer family mutation

Karla Wolf, Jan Kosinski, Toby J. Gibson, Nicole Wesch, Volker Dötsch, Maurizio Genuardi, Emanuela Lucci Cordisco, Stefan Zeuzem, Angela Brieger, Guido Plotz

Risultato della ricerca: Contributo in rivistaArticolo in rivista

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.
Lingua originaleEnglish
pagine (da-a)6307-6320
Numero di pagine14
RivistaNucleic Acids Research
Volume51
DOI
Stato di pubblicazionePubblicato - 2023

Keywords

  • CANCER

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