The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear periphery
Summary: Hairpin-forming CAG/CTG repeats pose significant challenges to DNA replication. In S. cerevisiae, long CAG/CTG repeat tracts reposition from the interior of the nucleus to the nuclear pore complex (NPC) to maintain their integrity. We show that relocation of a (CAG/CTG)130 tract to the NPC...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472500854X |
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| author | Tyler M. Maclay Jenna M. Whalen Matthew J. Johnson Catherine H. Freudenreich |
| author_facet | Tyler M. Maclay Jenna M. Whalen Matthew J. Johnson Catherine H. Freudenreich |
| author_sort | Tyler M. Maclay |
| collection | DOAJ |
| description | Summary: Hairpin-forming CAG/CTG repeats pose significant challenges to DNA replication. In S. cerevisiae, long CAG/CTG repeat tracts reposition from the interior of the nucleus to the nuclear pore complex (NPC) to maintain their integrity. We show that relocation of a (CAG/CTG)130 tract to the NPC is dependent on phosphorylation of Mrc1 (hClaspin) of the fork protection complex and activation of the Mrc1/Rad53 replication checkpoint, implicating an uncoupled fork as the initial damage signal. Dun1-mediated phosphorylation of the kinetochore protein Cep3 is required for repositioning, a constraint that can be overcome by centromere inactivation, connecting detachment of the kinetochore from microtubule ends to NPC association. Activation of this pathway leads to the formation of DNA damage-induced microtubules, which associate with the repeat and are necessary for locus repositioning. These data implicate the replication checkpoint in facilitating the movement of DNA structure-associated damage to the nuclear periphery by centromere release and microtubule-directed motion. |
| format | Article |
| id | doaj-art-06cdeec6b49841d8801b5a94d56a59e2 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-06cdeec6b49841d8801b5a94d56a59e22025-08-20T03:58:11ZengElsevierCell Reports2211-12472025-08-0144811608310.1016/j.celrep.2025.116083The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear peripheryTyler M. Maclay0Jenna M. Whalen1Matthew J. Johnson2Catherine H. Freudenreich3Department of Biology, Tufts University, Medford, MA 02155, USADepartment of Biology, Tufts University, Medford, MA 02155, USADepartment of Biology, Tufts University, Medford, MA 02155, USADepartment of Biology, Tufts University, Medford, MA 02155, USA; Corresponding authorSummary: Hairpin-forming CAG/CTG repeats pose significant challenges to DNA replication. In S. cerevisiae, long CAG/CTG repeat tracts reposition from the interior of the nucleus to the nuclear pore complex (NPC) to maintain their integrity. We show that relocation of a (CAG/CTG)130 tract to the NPC is dependent on phosphorylation of Mrc1 (hClaspin) of the fork protection complex and activation of the Mrc1/Rad53 replication checkpoint, implicating an uncoupled fork as the initial damage signal. Dun1-mediated phosphorylation of the kinetochore protein Cep3 is required for repositioning, a constraint that can be overcome by centromere inactivation, connecting detachment of the kinetochore from microtubule ends to NPC association. Activation of this pathway leads to the formation of DNA damage-induced microtubules, which associate with the repeat and are necessary for locus repositioning. These data implicate the replication checkpoint in facilitating the movement of DNA structure-associated damage to the nuclear periphery by centromere release and microtubule-directed motion.http://www.sciencedirect.com/science/article/pii/S221112472500854XCP: Molecular biology |
| spellingShingle | Tyler M. Maclay Jenna M. Whalen Matthew J. Johnson Catherine H. Freudenreich The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear periphery Cell Reports CP: Molecular biology |
| title | The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear periphery |
| title_full | The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear periphery |
| title_fullStr | The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear periphery |
| title_full_unstemmed | The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear periphery |
| title_short | The DNA replication checkpoint targets the kinetochore to reposition DNA structure-induced replication damage to the nuclear periphery |
| title_sort | dna replication checkpoint targets the kinetochore to reposition dna structure induced replication damage to the nuclear periphery |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S221112472500854X |
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