Microsatellite instability articles from across Nature Portfolio

Somatic expansion of a CAG repeat in HTT drives onset of Huntington’s disease. Using a human cell line model and splice modulators, here the authors show that PMS1 is an enhancer of CAG repeat expansion, making it a target for therapeutic intervention.

Exposure of a structure-forming sequence within a single-stranded gap creates a fragile site, resulting in large deletions. Gap filling drives disease-causing CAG repeat expansions, with direction of instability determined by the identity of the sequence on the template strand of the gap.

DNA replication of repetitive sequences was recreated in a test tube using purified components. DNA alone was sufficient to induce stalling. Both stalling and recovery were dictated by the capacity of DNA to fold into unusual secondary structures.

Defects in DNA mismatch repair (MMR) have been linked to inherited and sporadic cancers. Here the authors demonstrate that the DNA repair protein Rad27 (human FEN1) functions in one of three redundant mispair excision pathways, where its flap endonuclease activity catalyzes mispair excision.

Four papers report that cancer cells with microsatellite instability, which arises owing to defects in DNA mismatch repair, are selectively vulnerable to knockout of WRN, a RecQ family DNA helicase that could potentially be targeted with small molecules.

In 2018, advances were made in immunotherapy for colorectal cancers with microsatellite instability but, by contrast, immunotherapy studies in microsatellite-stable colorectal cancer had disappointing results. However, novel insights into the tumour microenvironment barriers that might limit therapeutic efficacy were identified, thereby offering new strategies.