Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells
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Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells. / Garribba, Lorenza; Bjerregaard, Victoria A; Gonçalves Dinis, Marisa M; Özer, Özgün; Wu, Wei; Sakellariou, Despoina; Pena-Diaz, Javier; Hickson, Ian D; Liu, Ying.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, No. 28, 2020, p. 16527-16536.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells
AU - Garribba, Lorenza
AU - Bjerregaard, Victoria A
AU - Gonçalves Dinis, Marisa M
AU - Özer, Özgün
AU - Wu, Wei
AU - Sakellariou, Despoina
AU - Pena-Diaz, Javier
AU - Hickson, Ian D
AU - Liu, Ying
N1 - Copyright © 2020 the Author(s). Published by PNAS.
PY - 2020
Y1 - 2020
N2 - Folate deprivation drives the instability of a group of rare fragile sites (RFSs) characterized by CGG trinucleotide repeat (TNR) sequences. Pathological expansion of the TNR within the FRAXA locus perturbs DNA replication and is the major causative factor for fragile X syndrome, a sex-linked disorder associated with cognitive impairment. Although folate-sensitive RFSs share many features with common fragile sites (CFSs; which are found in all individuals), they are induced by different stresses and share no sequence similarity. It is known that a pathway (termed MiDAS) is employed to complete the replication of CFSs in early mitosis. This process requires RAD52 and is implicated in generating translocations and copy number changes at CFSs in cancers. However, it is unclear whether RFSs also utilize MiDAS and to what extent the fragility of CFSs and RFSs arises by shared or distinct mechanisms. Here, we demonstrate that MiDAS does occur at FRAXA following folate deprivation but proceeds via a pathway that shows some mechanistic differences from that at CFSs, being dependent on RAD51, SLX1, and POLD3. A failure to complete MiDAS at FRAXA leads to severe locus instability and missegregation in mitosis. We propose that break-induced DNA replication is required for the replication of FRAXA under folate stress and define a cellular function for human SLX1. These findings provide insights into how folate deprivation drives instability in the human genome.
AB - Folate deprivation drives the instability of a group of rare fragile sites (RFSs) characterized by CGG trinucleotide repeat (TNR) sequences. Pathological expansion of the TNR within the FRAXA locus perturbs DNA replication and is the major causative factor for fragile X syndrome, a sex-linked disorder associated with cognitive impairment. Although folate-sensitive RFSs share many features with common fragile sites (CFSs; which are found in all individuals), they are induced by different stresses and share no sequence similarity. It is known that a pathway (termed MiDAS) is employed to complete the replication of CFSs in early mitosis. This process requires RAD52 and is implicated in generating translocations and copy number changes at CFSs in cancers. However, it is unclear whether RFSs also utilize MiDAS and to what extent the fragility of CFSs and RFSs arises by shared or distinct mechanisms. Here, we demonstrate that MiDAS does occur at FRAXA following folate deprivation but proceeds via a pathway that shows some mechanistic differences from that at CFSs, being dependent on RAD51, SLX1, and POLD3. A failure to complete MiDAS at FRAXA leads to severe locus instability and missegregation in mitosis. We propose that break-induced DNA replication is required for the replication of FRAXA under folate stress and define a cellular function for human SLX1. These findings provide insights into how folate deprivation drives instability in the human genome.
U2 - 10.1073/pnas.1921219117
DO - 10.1073/pnas.1921219117
M3 - Journal article
C2 - 32601218
VL - 117
SP - 16527
EP - 16536
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 - 28
ER -
ID: 244689285