New Roles for Canonical Transcription Factors in Repeat Expansion Diseases

Trends Genet. 2020 Feb;36(2):81-92. doi: 10.1016/j.tig.2019.11.003. Epub 2019 Dec 11.

Abstract

The presence of microsatellite repeat expansions within genes is associated with >30 neurological diseases. Of interest, (GGGGCC)>30-repeats within C9orf72 are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These expansions can be 100s to 1000s of units long. Thus, it is perplexing how RNA-polymerase II (RNAPII) can successfully transcribe them. Recent investigations focusing on GGGGCC-transcription have identified specific, canonical complexes that may promote RNAPII-transcription at these GC-rich microsatellites: the DSIF complex and PAF1C. These complexes may be important for resolving the unique secondary structures formed by GGGGCC-DNA during transcription. Importantly, this process can produce potentially toxic repeat-containing RNA that can encode potentially toxic peptides, impacting neuron function and health. Understanding how transcription of these repeats occurs has implications for therapeutics in multiple diseases.

Keywords: ALS/FTD; C9orf72; DSIF complex; Drosophila; PAF1C; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • C9orf72 Protein / genetics*
  • DNA Repeat Expansion / genetics*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / pathology
  • GC Rich Sequence / genetics
  • Humans
  • Microsatellite Repeats / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • Peptides / genetics
  • RNA / biosynthesis
  • RNA / genetics
  • RNA Polymerase II / genetics
  • Transcription Factors / genetics*
  • Transcription, Genetic*

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Peptides
  • Transcription Factors
  • RNA
  • RNA Polymerase II