The group of Dr. Andre Nussenzweig will investigate the molecular mechanisms causing GAA expansion and FXN gene silencing in Friedreich ataxia (FA) by examining the role of transcription in repeat expansion and formation of alternative DNA structures and testing whether molecules that reverse these structures will also block repeat expansion. Although the genetic cause of FA has been known for more than two decades, the molecular mechanisms causing (GAA)n expansion and FXN gene silencing remain unclear. One prevailing model to explain the FXN downregulation in FA cells is that alternative DNA secondary structures accumulate at this locus, which becomes a barrier to the productive elongation of FXN transcripts. Recently, the group of Dr. Andre Nussenzweig, in collaboration with Dr. Karen Usdin and Dr. Marek Napierala, developed methods that detected alternative DNA structures (DNA triplexes) in cells derived from Friedreich’s ataxia patients. Here, Dr. Nussenzweig joins forces with the Usdin and Napierala groups to determine the molecular basis for (GAA)n repeat instability and FXN gene silencing. The investigators will examine the role of transcription in repeat expansion. They will boost or reduce transcription of the FXN gene and determine how this affects the length of the GAA tract. They will also ask whether transcription is required for the formation of alternative DNA structures by boosting or reducing transcription of FXN and testing for triplex formation. Finally, the investigators plan to test whether molecules that reverse alternative DNA structure formation will also block repeat expansion. The hope is to identify efficient ways to prevent expansion or promote contraction in order to restore FXN gene expression.
General Research Grant | Mechanism or Pathway of Disease
Mechanism of repeat expansion in Friedreich’s ataxia
Grant Awarded | Mar 2023
Andre Nussenzweig, PhD
National Cancer Institute, NIH
Active

The FARA Grant Program is proud to award a General Research Grant to Andre Nussenzweig, PhD at National Cancer Institute, NIH.