The TRESLIN-MTBP complex couples completion of DNA replication with S/G2 transition

Zonderland, Gijs; Vanzo, Riccardo; Amitash, Sampath; Martín-Doncel, Elena; Coscia, Fabian; Mund, Andreas; Lerdrup, Mads; Benada, Jan; Boos, Dominik; Toledo, Luis I.

doi:10.1016/j.molcel.2022.08.006

Cited by 13 publications

(11 citation statements)

References 66 publications

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“…The dual function of the protein, at the fork as an ATR activator and at the pre-IC as a lock to GMGE emergence, in addition suggests a regulatory loop in which eviction of TopBP1 from the pre-ICs fuels its recruitment to slowed forks, favoring amplification of DRC signaling. Note that redistribution of the Treslin-MTBP complex has been recently shown to contribute to another regulatory loop that couples replication completion to the onset of G2 phase 24 . Together, these results highlight the importance of unessential pre-IC components in S phase fitness, which explains their key role in the maintenance of genome stability.…”

Section: Discussionmentioning

confidence: 99%

The balance between ATR and DDK activities controls TopBP1-mediated locking of dormant origins at the pre-IC stage

Koundrioukoff,

Kim,

Alary

et al. 2023

Preprint

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SummaryReplication stress, a major hallmark of cancers, and ensuing genome instability source from impaired progression of replication forks. The first line of defense against fork slowing is compensation, a long-described process that elicits firing of otherwise dormant origins. It remains unclear whether compensation requires activation of the DNA replication checkpoint or passively results from lengthening of the window of time during which dormant origins can fire when fork progression slows, or both. Using molecular DNA combing we show here that a linear relationship ties inter-origin distances to fork speeds, independently of the checkpoint status. We called this line “stressline” and further show that its slope enables precise quantification of the compensation efficiency. Comparison of the slopes in different genetic backgrounds reveals that compensation requires ATR, not CHK1, while TopBP1 and CDC7/DBF4 repress dormant origin activation. These results strongly suggest that TopBP1 locks dormant origins at the pre-IC stage and that ATR and DDK oppose to control the conversion of dormant pre-ICs into functional salvage origins. Both passive and active processes thus contribute to compensation. Moreover, Repli-seq and OK-seq analyses confirm the activating role of ATR and permit development of ATRAP-seq, a new procedure allowing mapping of early constitutive origins.

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Section: Discussionmentioning

confidence: 99%

The balance between ATR and DDK activities controls TopBP1-mediated locking of dormant origins at the pre-IC stage

Koundrioukoff,

Kim,

Alary

et al. 2023

Preprint

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“…The multiple RNA expression profiles were obtained from GEO [ https://www.ncbi.nlm.nih.gov/geo/ ). GEO datasets (GSE72094 ( 10 ), GSE50081 ( 11 ), GSE13213 ( 12 ), GSE30219 ( 13 ), GSE41271 ( 14 ), GSE42127 ( 15 ), GSE126044 ( 16 ), and GSE210129 ( 17 )] were enrolled to validate the prognosis value. After excluding samples without survival information, these datasets retained 398, 127, 116, 85, 182, and 133 samples, respectively.…”

Section: Methodsmentioning

confidence: 99%

TICRR serves as a prognostic biomarker in lung adenocarcinoma with implications in RNA epigenetic modification, DDR pathway, and RNA metabolism

Zheng,

Han,

Guan

et al. 2023

Front. Oncol.

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PurposeTOPBP1 interacting checkpoint and replication regulator (TICRR), a hub gene of the Cdk2-mediated initiation step of DNA replication, has been shown an essential role in tumorigenesis by accelerating the DNA replication of tumor cells.MethodsRT-qPCR was used to detect the mRNA expression of TICRR in LUAD tumors and adjacent normal tissues. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database of LUAD were acquired to analyze the critical role of TICRR expression in survival prognosis and clinicopathology characters in LUAD. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were performed using the R package. The correlation of TICRR expression with immune cell infiltration, RNA epigenetic modification, DNA damage repair (DDR) pathway, and cell metabolism of LUAD was further explored to verify significant conclusions.ResultsTICRR was significantly upregulated in most cancer types, including LUAD, lung squamous cell carcinoma (LUSC), and others. Cox regression analysis indicated the overexpression of TICRR was associated with poor survival in several cancers. In LUAD, TICRR expression was positively correlated with tumor stage and was increased in smoking, male, and high tumor mutational burden (TMB) patients. Enrichment analysis revealed that TICRR could influence tumor proliferation and prognosis via activating pathways involving cell cycle, DNA repair, DNA replication, cysteine metabolism, oxidative phosphorylation, and ubiquitin-mediated proteolysis pathways. Interestingly, high TICRR expression correlated with DDR pathway signature (34 genes), 37 m6A/m5C regulated genes, and some metabolism-regulated genes. Silencing the TICRR gene affects cysteine metabolism and modifies cancer-related pathways, with decreased cell cycle and increased B/T cell receptor signaling. Our TICRR risk model accurately predicts LUAD patient prognosis, validated across GEO datasets, and is integrated with clinical characteristics via a nomogram, facilitating personalized treatment strategies and enhancing patient management.ConclusionsTaken together, TICRR has emerged as a promising prognostic biomarker in lung adenocarcinoma (LUAD), with implications in immune activation, cell cycle regulation, RNA modification, and tumor energy metabolism. These findings suggest that TICRR could serve as a viable therapeutic target and a reliable prognostic indicator for LUAD.

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“…In cycling cells with depleted CHK1 gene, premature mitotic entry was observed when mildly under-replicated DNA occurred at the end of the S-phase [ 90 , 91 ]. This was due to a low threshold of origin firing [ 92 ]. In this way, unfinished replication can continue during the G2 phase and during G2/M transition, but with a lower intensity [ 48 , 93 ].…”

Section: Chk1 As Regulator Of Dna Damage Checkpointmentioning

confidence: 99%

Checkpoint Kinase 1 Is a Key Signal Transducer of DNA Damage in the Early Mammalian Cleavage Embryo

Baran

Mayer

2023

IJMS

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After fertilization, remodeling of the oocyte and sperm genome is essential for the successful initiation of mitotic activity in the fertilized oocyte and subsequent proliferative activity of the early embryo. Despite the fact that the molecular mechanisms of cell cycle control in early mammalian embryos are in principle comparable to those in somatic cells, there are differences resulting from the specific nature of the gene totipotency of the blastomeres of early cleavage embryos. In this review, we focus on the Chk1 kinase as a key transduction factor in monitoring the integrity of DNA molecules during early embryogenesis.

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The TRESLIN-MTBP complex couples completion of DNA replication with S/G2 transition

Cited by 13 publications

References 66 publications

The balance between ATR and DDK activities controls TopBP1-mediated locking of dormant origins at the pre-IC stage

The balance between ATR and DDK activities controls TopBP1-mediated locking of dormant origins at the pre-IC stage

TICRR serves as a prognostic biomarker in lung adenocarcinoma with implications in RNA epigenetic modification, DDR pathway, and RNA metabolism

Checkpoint Kinase 1 Is a Key Signal Transducer of DNA Damage in the Early Mammalian Cleavage Embryo

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