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Last update 08 May 2025

MRN

Last update 08 May 2025

Basic Info

Synonyms-

Introduction-

Drugs associated with MRN

VIO-01

Target

Ku70/80 x MRN x PARP1

Mechanism

Ku70/80 inhibitors [+2]

Active Org.-

Originator Org.

Valerio Therapeutics SA

Active Indication-

Inactive Indication

HRR Gene-mutated Castration-Resistant Prostate Cancer [+4]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with MRN

NCT06257758

/ TerminatedPhase 1/2

A Phase 1/2 Study of VIO-01 in Participants With Recurrent Solid Tumors

The goal of this phase 1/2 clinical trial is to investigate the safety of an investigational drug called VIO-01 when taken by people who have different types of solid tumor cancers. There are two parts to this trial, part 1 and part 2.
Part 1 of the trial aims to answer these questions:
* The safety and tolerability of VIO-01 when it is given alone or in combination with other anti-cancer therapies.
* The highest dose that people can take without having unacceptable side effects
* How well your body tolerates the drug alone or in combination, how they are absorbed, and the effects they have on your disease.
Part 2 of the trial will further test VIO-01's effect in participants with advanced HRRm or HRD+ solid tumors and HRRm/HRD+ recurrent ovarian cancer.
Participants will follow a schedule of visits to the study site to have assessments done related to their health condition and to receive the trial treatment.

Start Date10 Jan 2024

Sponsor / Collaborator

Valerio Therapeutics SA

100 Clinical Results associated with MRN

100 Translational Medicine associated with MRN

0 Patents (Medical) associated with MRN

664

Literatures (Medical) associated with MRN

01 Jul 2025·Plant Physiology and Biochemistry

NBS1 from Physcomitrium patens confers resistance against oxidative stress through the BRCA1 C-terminus (BRCT) domain, independent of the MRE11 interaction

Article

Author: Das, Arup ; Ray, Sudipta ; Singh, Kajal ; Halder, Tanmoy

The Nijmegen breakage syndrome 1 (NBS1) protein is a core member of the MRE11-RAD50-NBS1 (MRN) complex and is known to function as a DNA damage sensor within the plant DNA damage response (DDR) pathway. We previously reported that NBS1 from Physcomitrium patens (PpNBS1) also plays a pivotal role in the defense against oxidative damage by reducing the level of cellular reactive oxygen species (ROS). Our study demonstrated that overexpression of PpNBS1 induces the expression of antioxidant genes involved in ROS scavenging in transgenic tobacco plants, leading to reduced accumulation of hydrogen peroxide (H₂O₂) and superoxide (O₂•^-). In this study, we generated N-terminal and C-terminal truncation mutants of the protein to selectively eliminate specific functional domains to characterize the role of PpNBS1 in cellular ROS detoxification. Transgenic tobacco plants overexpressing PpNBS1 truncation mutants were generated and evaluated for their oxidative stress tolerance. PpNBS1 mutant plants lacking the BRCA1 C-terminal (BRCT) domain exhibited compromised stress tolerance. Our findings underscore the importance of the N-terminal BRCT domain of PpNBS1 in oxidative stress tolerance and provide evidence that the BRCT domain is crucial for the increased expression of ROS-scavenging enzymes. Furthermore, our findings confirm that the C-terminal region of PpNBS1 is critical for its binding with PpMRE11 (Meiotic recombination 11). Nevertheless, transgenic plants expressing the PpNBS1 mutant lacking the NBS_C terminal domain presented resistance to oxidative stress comparable to that of PpNBS1-transgenic plants. Overall, we deduce that PpNBS1 protects against oxidative stress via the BRCT domain, regardless of its interaction with MRE11.

01 May 2025·Ecotoxicology and Environmental Safety

Adolescent cetylpyridinium chloride exposure impairs homologous recombination repair and induces granulosa cell apoptosis and follicular atresia via FOXM1/CREBBP complex suppression

Article

Author: Yin, Xin ; Geng, Yanqing ; He, Junlin ; Ma, Yidan ; Zhang, Yan ; Mu, Xinyi ; Gao, Rufei ; Chen, Xuemei ; Ma, LiYao

Cetylpyridinium chloride (CPC), a widely used surfactant, functions as an antimicrobial agent in pharmaceuticals and personal care products (PPCPs). However, its effect on the female reproductive system remains largely unknown. Herein, female mice were gavaged with 0.01, 0.1, or 1 mg CPC/kg body weight (bw)/d during adolescence. Results showed reduced body and ovarian weights, decreased primordial follicle numbers, and increased atretic follicles. Additionally, CPC disrupted serum hormone levels, reduced cell viability and proliferation, and increased apoptosis in granulosa cells. Transcriptomic analysis of primary granulosa cells revealed altered genes in homologous recombination (HR) repair pathway, including the downregulation of FOXM1 and the MRN complex. Further validation demonstrated decreased expression of HR repair components and increased DNA damage in both in vivo and in vitro. Mechanistically, CPC inhibited the FOXM1/CREBBP interaction and inhibited HR repair gene transcription, including MRE11 and NBS1. Finally, FOXM1 overexpression partially reversed the detrimental effects of CPC on HR repair and cell proliferation. These results indicate that CPC-induced ovarian dysfunction during adolescence is mediated through FOXM1/CREBBP complex inhibition and homologous recombination repair impairment, potentially increasing the risk for the development of diminished ovarian reserve (DOR) and providing new experimental evidence to assess the reproductive toxicity effects of CPC.

22 Apr 2025·Proceedings of the National Academy of Sciences

ATM priming and end resection–coupled phosphorylation of MRE11 is important for fork protection and replication restart

Article

Author: Oaks, Joshua ; Wang, Hailong ; Shah, Sameer Bikram ; Li, Qingrong ; Wang, Dong ; Li, Youhang ; Lv, Tinghong ; Zhang, Huimin ; Li, Shibo ; Shi, Linda Z. ; Wu, Xiaohua

The MRE11/RAD50/NBS1 (MRN) complex plays multiple roles in the maintenance of genome stability. MRN is associated with replication forks to preserve fork integrity and is also required for end resection at double-strand breaks (DSBs) to facilitate homologous recombination (HR). The critical need for proper control of the MRE11 nuclease activity is highlighted by the extensive nascent strand DNA degradation driven by MRE11 in BRCA-deficient cells, leading to genome instability and increased sensitivity to chemotherapeutics. In this study, we identified a tightly controlled mechanism, elicited by sequential phosphorylation of MRE11 by ATM and ATR to regulate MRE11 nuclease activities through its DNA binding. Specifically, at DSBs, MRE11 phosphorylation by ATM at the C-terminal S676/S678 primes it for subsequent phosphorylation by ATR, whose activation is triggered by end resection which requires the MRE11 nuclease activity. This ATR-mediated phosphorylation in turn induces MRE11 dissociation from DNA, providing a feedback mechanism to regulate the extent of end resection. At stalled replication forks, however, without ATM priming, MRN is stably associated with forks despite ATR activation. Furthermore, the ATR phosphorylation–defective MRE11 mutants are retained at single-ended DSBs formed by fork reversal upon replication stress, leading to extensive degradation of nascent DNA strands. Importantly, this end resection–coupled MRE11 phosphorylation elicits another critical layer of fork protection of nascent DNA in addition to BRCA2, ensuring proper end resection that is sufficient for replication restart at reversed forks while maintaining fork stability.

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