Retraction: Tripeptidyl-Peptidase II Controls DNA Damage Responses and In Vivo γ-Irradiation Resistance of Tumors

AbstractWe combine a systems pharmacology approach with an agent-based modelling approach to simulate LoVo cells subjected to AZD6738, an ATR (ataxia–telangiectasia-mutated and rad3-related kinase) inhibiting anti-cancer drug that can hinder tumour proliferation by targeting cellular DNA damage responses. The agent-based model used in this study is governed by a set of empirically observable rules. By adjusting only the rules when moving between monolayer and multi-cellular tumour spheroid simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model is first parameterised by monolayer in vitro data and is thereafter used to simulate treatment responses in in vitro tumour spheroids subjected to dynamic drug delivery. Spheroid simulations are subsequently compared to in vivo data from xenografts in mice. The spheroid simulations are able to capture the dynamics of in vivo tumour growth and regression for approximately 8 days post-tumour injection. Translating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and in this article, we exemplify how data-driven, agent-based models can be used to bridge the gap between in vitro and in vivo research. We further highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

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Banp regulates DNA damage response and chromosome segregation during the cell cycle in zebrafish retina

10.1101/2021.11.03.467208 ◽

2021 ◽

Author(s):

Swathy Babu ◽

Yuki Takeuchi ◽

Ichiro Masai

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Replication ◽

Dna Damage Response ◽

Chromosome Segregation ◽

Cell Cycle Progression ◽

Target Genes ◽

Damage Response ◽

Dna Damage Responses

Btg3-associated nuclear protein (Banp) was originally identified as a nuclear matrix-associated protein and it functions as a tumor suppressor. At molecular level, Banp regulates transcription of metabolic genes via a CGCG-containing motif called the Banp motif. However, its physiological roles in embryonic development are unknown. Here we report that Banp is indispensable for DNA damage response and chromosome segregation during mitosis. Zebrafish banp mutants show mitotic arrest and apoptosis in developing retina. We found that DNA replication stress and tp53-dependent DNA damage responses were activated to induce apoptosis in banp mutants, suggesting that Banp is required for integrity of DNA replication and DNA damage repair. Furthermore, in banp mutants, chromosome segregation was not smoothly processed from prometaphase to anaphase, leading to a prolonged M-phase. Our RNA- and ATAC-sequencing identified 31 candidates for direct Banp target genes that carry the Banp motif. Interestingly, two chromosome segregation regulators, cenpt and ncapg, are included in this list. Thus, Banp directly regulates transcription of cenpt and ncapg to promote chromosome segregation during mitosis. Our findings provide the first in vivo evidence that Banp is required for cell-cycle progression and cell survival by regulating DNA damage responses and chromosome segregation during mitosis.

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Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1714938115 ◽

2018 ◽

Vol 115 (18) ◽

pp. 4678-4683 ◽

Cited By ~ 44

Author(s):

Tanggang Deng ◽

Guobei Yan ◽

Xin Song ◽

Lin Xie ◽

Yu Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Fate ◽

Cell Cycle Progression ◽

Kinase Inhibitor ◽

Independent Manner ◽

Cycle Progression ◽

Dna Damage Responses ◽

Fate Decision

p21WAF1/CIP1 is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell-cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligase complexes is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report USP11 as a deubiquitylase of p21. In the nucleus, USP11 binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21, and stabilizes p21 protein. As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCFSKP2, CRL4CDT2, and APC/CCDC20 in a cell-cycle–independent manner. Loss of USP11 causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of USP11, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally, USP11-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation, and they pinpoint a crucial role of the USP11-p21 axis in regulating cell-cycle progression and DNA damage responses.

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