Folate deficiency drives mitotic missegregation of the human FRAXA locus

Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):13003-13008. doi: 10.1073/pnas.1808377115. Epub 2018 Dec 3.

Abstract

The instability of chromosome fragile sites is implicated as a causative factor in several human diseases, including cancer [for common fragile sites (CFSs)] and neurological disorders [for rare fragile sites (RFSs)]. Previous studies have indicated that problems arising during DNA replication are the underlying source of this instability. Although the role of replication stress in promoting instability at CFSs is well documented, much less is known about how the fragility of RFSs arises. Many RFSs, as exemplified by expansion of a CGG trinucleotide repeat sequence in the fragile X syndrome-associated FRAXA locus, exhibit fragility in response to folate deficiency or other forms of "folate stress." We hypothesized that such folate stress, through disturbing the replication program within the pathologically expanded repeats within FRAXA, would lead to mitotic abnormalities that exacerbate locus instability. Here, we show that folate stress leads to a dramatic increase in missegregation of FRAXA coupled with the formation of single-stranded DNA bridges in anaphase and micronuclei that contain the FRAXA locus. Moreover, chromosome X aneuploidy is seen when these cells are exposed to folate deficiency for an extended period. We propose that problematic FRAXA replication during interphase leads to a failure to disjoin the sister chromatids during anaphase. This generates further instability not only at FRAXA itself but also of chromosome X. These data have wider implications for the effects of folate deficiency on chromosome instability in human cells.

Keywords: CGG trinucleotide repeats; FRAXA; RPA UFB; chromosome missegregation; folate deficiency.

Publication types

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

MeSH terms

  • Cells, Cultured
  • Chromosome Fragile Sites*
  • Chromosomes, Human, X*
  • DNA Replication
  • Folic Acid / metabolism*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / metabolism
  • Fragile X Syndrome / pathology*
  • Humans
  • Lymphocytes / metabolism
  • Lymphocytes / pathology*
  • Male
  • Mitosis*
  • Stress, Physiological*
  • Trinucleotide Repeat Expansion

Substances

  • FMR1 protein, human
  • Fragile X Mental Retardation Protein
  • Folic Acid