TY - JOUR
T1 - Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation
AU - Gerhardt, Jeannine
AU - Zaninovic, Nikica
AU - Zhan, Qiansheng
AU - Madireddy, Advaitha
AU - Nolin, Sarah L.
AU - Ersalesi, Nicole
AU - Yan, Zi
AU - Rosenwaks, Zev
AU - Schildkraut, Carl L.
PY - 2014
Y1 - 2014
N2 - Fragile X syndrome (FXS) is caused by CGG repeat expansion that leads to FMR1 silencing. Women with a premutation allele are at risk of having a full mutation child with FXS. To investigate the mechanism of repeat expansion, we examined the relationship between a singlenucleotide polymorphism (SNP) variant that is linked to repeat expansion in haplogroup D and a replication origin located ∼53 kb upstream of the repeats. This origin is absent in FXS human embryonic stem cells (hESCs), which have the SNP variant C, but present in the nonaffected hESCs, which have a T variant. The SNP maps directly within the replication origin. Interestingly, premutation hESCs have a replication origin and the T variant similar to nonaffected hESCs. These results suggest that a T/C SNP located at a replication origin could contribute to the inactivation of this replication origin in FXS hESCs, leading to altered replication fork progression through the repeats, which could result in repeat expansion to the FXS full mutation.
AB - Fragile X syndrome (FXS) is caused by CGG repeat expansion that leads to FMR1 silencing. Women with a premutation allele are at risk of having a full mutation child with FXS. To investigate the mechanism of repeat expansion, we examined the relationship between a singlenucleotide polymorphism (SNP) variant that is linked to repeat expansion in haplogroup D and a replication origin located ∼53 kb upstream of the repeats. This origin is absent in FXS human embryonic stem cells (hESCs), which have the SNP variant C, but present in the nonaffected hESCs, which have a T variant. The SNP maps directly within the replication origin. Interestingly, premutation hESCs have a replication origin and the T variant similar to nonaffected hESCs. These results suggest that a T/C SNP located at a replication origin could contribute to the inactivation of this replication origin in FXS hESCs, leading to altered replication fork progression through the repeats, which could result in repeat expansion to the FXS full mutation.
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U2 - 10.1083/jcb.201404157
DO - 10.1083/jcb.201404157
M3 - Article
C2 - 25179629
AN - SCOPUS:84906846861
SN - 0021-9525
VL - 206
SP - 599
EP - 607
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
ER -