The competing mini-dumbbell mechanism: new insights into CCTG repeat expansion.

Pei Guo,Sik Lok Lam

doi:10.1038/sigtrans.2016.28

Abstract

CCTG repeat expansions in intron 1 of the cellular nucleic acid-binding protein gene are associated with myotonic dystrophy type 2. Recently, we have reported a novel mini-dumbbell (MDB) structure formed by two CCTG or TTTA repeats, which potentially has a critical role in repeat expansions. Here we present a mechanism, called the competing MDB mechanism, to explain how the formation of MDB can lead to efficient mismatch repair (MMR) escape and thus CCTG repeat expansions during DNA replication. In a long tract of CCTG repeats, two competing MDBs can be formed in any segment of three repeats. Fast exchange between these MDBs will make the commonly occupied repeat behave like a mini-loop. Further participations of the 5′- or 3′-flanking repeat in forming competing MDBs will make the mini-loop shift in the 5′- or 3′-direction, thereby providing a pathway for the mini-loop to escape from MMR. To avoid the complications due to the formation of hairpin conformers in longer CCTG repeats, we made use of TTTA repeats as model sequences to demonstrate the formation of competing MDBs and shifting of mini-loop in a long tract of repeating sequence.

Highlights

Expansions of CCTG repeats found in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene on chromosome 3q21 are associated with a complex multisystem disorder called myotonic dystrophy type 2 (DM2).[1]
The unusual structure will be recognized and removed by mismatch repair (MMR), which is a post-replication repair system to maintain the fidelity of DNA replication
We present a novel mechanism, called the competing MDB mechanism, to explain how efficient MMR escape can occur via the formation of MDBs

Summary

Introduction

Expansions of CCTG repeats found in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene on chromosome 3q21 are associated with a complex multisystem disorder called myotonic dystrophy type 2 (DM2).[1]. (TTTA)[4] behaves like a mini-loop at the third repeat In a DNA strand containing four TTTA repeats, three types of MDBs can be formed using the first two, the middle two and the last two repeats, respectively.

Results

Conclusion