Folate deficiency drives mitotic missegregation of the human FRAXA locus
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Folate deficiency drives mitotic missegregation of the human FRAXA locus. / Bjerregaard, Victoria A; Garribba, Lorenza; McMurray, Cynthia T; Hickson, Ian D; Liu, Ying.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 51, 2018, p. 13003-13008.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Folate deficiency drives mitotic missegregation of the human FRAXA locus
AU - Bjerregaard, Victoria A
AU - Garribba, Lorenza
AU - McMurray, Cynthia T
AU - Hickson, Ian D
AU - Liu, Ying
N1 - Copyright © 2018 the Author(s). Published by PNAS.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - CGG trinucleotide repeats
KW - Chromosome missegregation
KW - Folate deficiency
KW - FRAXA
KW - RPA UFB
KW - folate deficiency
KW - chromosome missegregation
U2 - 10.1073/pnas.1808377115
DO - 10.1073/pnas.1808377115
M3 - Journal article
C2 - 30509972
VL - 115
SP - 13003
EP - 13008
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 51
ER -
ID: 209829899