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Replication stress induces POLQ-mediated structural variant formation throughout common fragile sites after entry into mitosis
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Replication stress induces POLQ-mediated structural variant formation throughout common fragile sites after entry into mitosis
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Journal Article
Replication stress induces POLQ-mediated structural variant formation throughout common fragile sites after entry into mitosis
2024
Overview
Genomic structural variants (SVs) greatly impact human health, but much is unknown about the mechanisms that generate the largest class of nonrecurrent alterations. Common fragile sites (CFSs) are unstable loci that provide a model for SV formation, especially large deletions, under replication stress. We study SV junction formation as it occurs in human cell lines by applying error-minimized capture sequencing to CFS DNA harvested after low-dose aphidicolin treatment. SV junctions form throughout CFS genes at a 5-fold higher rate after cells pass from G2 into M-phase. Neither SV formation nor CFS expression depend on mitotic DNA synthesis (MiDAS), an error-prone form of replication active at CFSs. Instead, analysis of tens of thousands of de novo SV junctions combined with DNA repair pathway inhibition reveal a primary role for DNA polymerase theta (POLQ)-mediated end-joining (TMEJ). We propose an important role for mitotic TMEJ in nonrecurrent SV formation genome wide.
The mechanisms of nonrecurrent structural variant (SV) formation are poorly understood. Here, the authors sequenced thousands of SV junctions as they formed at common fragile sites in human cell lines to reveal a primary role for DNA polymerase theta-mediated end joining activated during mitosis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ 45/22
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/ 45/41
/ 45/77
/ 82/1
/ 82/29
/ Chromosome Fragile Sites - genetics
/ DNA
/ DNA-Directed DNA Polymerase - genetics
/ DNA-Directed DNA Polymerase - metabolism
/ Genomic Structural Variation
/ Humanities and Social Sciences
/ Humans
/ Mitosis
/ Science
