DNA Extrusion Size Determines Pathway Choice during CAG Repeat Expansion

Dr. Anna Pluciennik, Associate Professor in the Department of Biochemistry and Molecular Biology , and her team have recently made discoveries that provide a mechanistic understanding of the factors that drive CAG repeat expansion.  This expansion is the underlying genetic cause of neurodegenerative pathologies such as Huntington’s disease. The study, which was published recently in Nucleic Acids Research, reveals a critical pathway choice mechanism governed by the topological properties exhibited by the DNA during the creation of the CAG expansions. The authors show that tiny loops (called extrahelical extrusions) that form when the strands of a DNA double helix containing repetitive DNA slip out of register are handled differently by the cell’s repair machinery depending on their size. When these loops contain a single repeat, they are preferentially recognized by a repair protein (MutSb) that mistakenly promotes further expansion of the repeats. Larger loops (two to three repeats), however, are often removed by the FAN1 nuclease, an enzyme that protects against expansion. Thus, for larger loops, the genetic outcome (expansion versus no expansion) is determined by competition between MutSb and FAN1. This means the size of the DNA distortion itself helps dictate whether the DNA sequence will become more unstable or stay the same, providing new insight into how harmful repeat expansions occur at the molecular level.  Dr. Mayuri Bhatia, a senior member of Dr. Pluciennik’s research team, led these studies in collaboration with other members of the group.