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Perturbation on DNA replication by cohesin dysfunction leads to gross genomic damages [PEM-seq-mutant]

ABSTRACT: Cohesin mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to gross DNA breaks and consequently elevates genome-wide chromosomal translocation levels up to five-fold in mammalian cells. These damages are independent of transcription alteration and loop anchor robustness. However, identified translocations occur asymmetrically on the chromatin Watson and Crick strands, coincident with Okazaki fragments of DNA replication. Moreover, early DNA replication initiates at about one thousand extra dormant origins after RAD21 depletion, which is independent of CTCF, resulting in earlier replicating timing at approximately 30% or 13% of the human or mouse genomic regions, respectively. And the translocation hotspot genes arising in RAD21-depleted cells are accompanied by dysregulated replication timing. Therefore, we conclude that cohesin dysfunction leads to perturbed DNA replication timing, which further results in gross DNA damages that may be involved in tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211347 | GEO | 2023/05/18

REPOSITORIES: GEO

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Perturbation on DNA replication by cohesin dysfunction leads to gross genomic damages [END-seq]

Project description:Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive DNA breaks, up to five-fold, and 147 translocation hotspot genes that are co-mutated with cohesin in multiple cancers. DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor elimination. However, translocation junctions coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes severe replication stresses induced by extra DNA replication, resulting in gross DNA damages that may induce tumorigenesis.

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Perturbation on DNA replication by cohesin dysfunction leads to gross genomic damages [NAIL-seq mES-EdUHU]

Project description:Cohesin mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to gross DNA breaks and consequently elevates genome-wide chromosomal translocation levels up to five-fold in mammalian cells. These damages are independent of transcription alteration and loop anchor robustness. However, identified translocations occur asymmetrically on the chromatin Watson and Crick strands, coincident with Okazaki fragments of DNA replication. Moreover, early DNA replication initiates at about one thousand extra dormant origins after RAD21 depletion, which is independent of CTCF, resulting in earlier replicating timing at approximately 30% or 13% of the human or mouse genomic regions, respectively. And the translocation hotspot genes arising in RAD21-depleted cells are accompanied by dysregulated replication timing. Therefore, we conclude that cohesin dysfunction leads to perturbed DNA replication timing, which further results in gross DNA damages that may be involved in tumorigenesis.

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Project description:Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks, up to five-fold, and 147 translocation hotspot genes that are co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor elimination. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.

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Cohesin maintains replication timing to suppress DNA damage on cancer genes [PEM-seq]

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Cohesin maintains replication timing to suppress DNA damage on cancer genes [HU120-CBE_NAIL-seq_END-seq]

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Project description:Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks, up to five-fold, and 147 translocation hotspot genes that are co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor elimination. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.

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Cohesin maintains replication timing to suppress DNA damage on cancer genes [q3C-seq]

Project description:Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks, up to five-fold, and 147 translocation hotspot genes that are co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor elimination. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.

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