RT Journal Article
SR Electronic
T1 Structural destabilization and chaperone-assisted proteasomal degradation of MLH1 as a mechanism for Lynch syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 622266
DO 10.1101/622266
A1 Amanda B. Abildgaard
A1 Amelie Stein
A1 Katrine Schultz-Knudsen
A1 Sofie V. Nielsen
A1 Elena Papaleo
A1 Amruta Shrikhande
A1 Eva R. Hoffmann
A1 Inge Bernstein
A1 Anne-Marie Gerdes
A1 Masanobu Takahashi
A1 Chikashi Ishioka
A1 Kresten Lindorff-Larsen
A1 Rasmus Hartmann-Petersen
YR 2019
UL http://biorxiv.org/content/early/2019/04/29/622266.abstract
AB A defective DNA mismatch repair (MMR) system leads to increased mutation rates and microsatellite instability. Accordingly, germline loss-of-function variants in any of the MMR components MSH2, MSH6, MLH1 and PMS2 are closely linked to the hereditary cancer predisposition disorder known as Lynch syndrome. As an early diagnosis increases survival, the identification of pathogenic variants in the MMR components is clinically important, but often complicated by many variants being of unknown pathogenic significance. Here we show that several disease-linked MLH1 protein variants are targeted by HSP70 for chaperone-assisted proteasomal degradation and are therefore present at reduced cellular amounts. In turn, this lower amount of MLH1 results in degradation of the MLH1-binding proteins PMS1 and PMS2. In silico saturation mutagenesis and computational prediction of the thermodynamic stability of all structurally-resolved MLH1 single-site missense variants revealed a correlation between the structural destabilization of MLH1, the reduced steady-state levels and loss-of-function. Accordingly, the thermodynamic stability predictions separate disease-linked MLH1 missense mutations from benign MLH1 variants, and therefore hold potential for classification of MLH1 missense variants of unknown consequence, and hence for Lynch syndrome diagnostics.