Replication stress induces POLQ-mediated structural variant formation throughout common fragile sites after entry into mitosis DOI Creative Commons
Thomas E. Wilson, Samreen Ahmed, Amanda Winningham

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Ноя. 6, 2024

Abstract Genomic structural variants (SVs) greatly impact human health, but much is unknown about the mechanisms that generate largest class of nonrecurrent alterations. Common fragile sites (CFSs) are unstable loci provide a model for SV formation, especially large deletions, under replication stress. We study junction formation as it occurs in cell lines by applying error-minimized capture sequencing to CFS DNA harvested after low-dose aphidicolin treatment. junctions form throughout genes at 5-fold higher rate cells pass from G2 into M-phase. Neither nor expression depend on mitotic synthesis (MiDAS), an error-prone active CFSs. Instead, analysis tens thousands de novo combined with repair pathway inhibition reveal primary role polymerase theta (POLQ)-mediated end-joining (TMEJ). propose important TMEJ genome wide.

Язык: Английский

FANCM branchpoint translocase: Master of traverse, reverse and adverse DNA repair DOI
Lara Abbouche, Rohan Bythell‐Douglas, Andrew J. Deans

и другие.

DNA repair, Год журнала: 2024, Номер 140, С. 103701 - 103701

Опубликована: Июнь 5, 2024

Язык: Английский

Процитировано

5
Cell Type Specific Suppression of Hyper-Recombination by Human RAD18 Is Linked to Proliferating Cell Nuclear Antigen K164 Ubiquitination DOI Creative Commons
Colette B. Rogers,

Wendy Leung,

Ryan M. Baxley

и другие.

Biomolecules, Год журнала: 2025, Номер 15(1), С. 150 - 150

Опубликована: Янв. 20, 2025

RAD18 is a conserved eukaryotic E3 ubiquitin ligase that promotes genome stability through multiple pathways. One of these gap-filling DNA synthesis at active replication forks and in post-replicative DNA. also regulates homologous recombination (HR) repair breaks; however, the current literature describing contribution to HR mammalian systems has not reached consensus. To investigate this, we examined three independent RAD18-null human cell lines. Our analyses found loss HCT116, but neither hTERT RPE-1 nor DLD1 lines, resulted elevated sister chromatid exchange, gene conversion, targeting, i.e., HCT116 mutants were hyper-recombinogenic (hyper-rec). Interestingly, phenotypes linked RAD18’s role PCNA K164 ubiquitination, as PCNAK164R/+ hyper-rec, consistent with previous studies rad18−/− pcnaK164R avian DT40 cells. Importantly, knockdown UBC9 prevent SUMOylation did affect hyper-recombination, strengthening link between increased RAD18-catalyzed SUMOylation. We propose hierarchy HR, intrinsic each type, dictates whether required for suppression hyper-recombination this function ubiquitination.

Язык: Английский

Процитировано

0
POLQ mediates replication-stress induced structural variant formation throughout common fragile sites during mitosis DOI Creative Commons
Thomas E. Wilson, Samreen Ahmed, Amanda Winningham

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 29, 2024

Abstract Genomic structural variants (SVs) greatly impact human health and disease, but much is unknown about their generative mechanisms, especially for the large class of nonrecurrent alterations. Common fragile sites (CFSs) are unstable loci that provide a model SV formation, deletions, under replication stress. We studied junction formation as it occurred in cells by applying error-minimized capture sequencing to CFS DNA harvested during junctions formed throughout genes at 5-fold higher rate after passed from G2 into M-phase. Neither nor expression depended on mitotic synthesis (MiDAS), an error-prone form conservative active CFSs. Instead, analysis tens thousands de novo combined with repair pathway inhibition revealed primary role polymerase theta (POLQ)-mediated end-joining (TMEJ) M-phase formation. propose important TMEJ genome wide.

Язык: Английский

Процитировано

1
New Insights into the Fanconi Anemia Pathogenesis: A Crosstalk Between Inflammation and Oxidative Stress DOI Open Access
Anna Repczyńska, Barbara Ruszkowska-Ciastek, Olga Haus

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(21), С. 11619 - 11619

Опубликована: Окт. 29, 2024

Fanconi anemia (FA) represents a rare hereditary disease; it develops due to germline pathogenic variants in any of the 22 currently discovered FANC genes, which interact with anemia/breast cancer-associated (FANC/BRCA) pathway maintain genome integrity. FA is characterized by triad clinical traits, including congenital anomalies, bone marrow failure (BMF) and multiple cancer susceptibility. Due complex genetic background broad spectrum symptoms, diagnostic process requires use classical cytogenetic, molecular cytogenetics strictly methods. Recent findings indicate interplay inflammation, oxidative stress, disrupted mitochondrial metabolism, impaired intracellular signaling pathogenesis. Additionally, shift balance towards overproduction proinflammatory cytokines prooxidant components associated advanced myelosuppression ultimately BMF. Although mechanism BMF very needs further clarification, appears that mutual interaction between redox imbalance causes pancytopenia. In this review, we summarize available literature regarding phenotype, background, procedures FA. We also highlight current understanding autophagy process, state, pathways genotoxic stress

Язык: Английский

Процитировано

0
Replication stress induces POLQ-mediated structural variant formation throughout common fragile sites after entry into mitosis DOI Creative Commons
Thomas E. Wilson, Samreen Ahmed, Amanda Winningham

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Ноя. 6, 2024

Abstract Genomic structural variants (SVs) greatly impact human health, but much is unknown about the mechanisms that generate largest class of nonrecurrent alterations. Common fragile sites (CFSs) are unstable loci provide a model for SV formation, especially large deletions, under replication stress. We study junction formation as it occurs in cell lines by applying error-minimized capture sequencing to CFS DNA harvested after low-dose aphidicolin treatment. junctions form throughout genes at 5-fold higher rate cells pass from G2 into M-phase. Neither nor expression depend on mitotic synthesis (MiDAS), an error-prone active CFSs. Instead, analysis tens thousands de novo combined with repair pathway inhibition reveal primary role polymerase theta (POLQ)-mediated end-joining (TMEJ). propose important TMEJ genome wide.

Язык: Английский

Процитировано

0