更新于：2024-11-01

RMI2 x RMI1 x FANCM

更新于：2024-11-01

基本信息

关联

项与 RMI2 x RMI1 x FANCM 相关的药物

PIP-199

靶点

FANCM x RMI1 x RMI2

作用机制

FANCM抑制剂 [+2]

在研机构

The University of Sydney

原研机构

The University of Sydney

在研适应症

Bloom综合征 [+1]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RMI2 x RMI1 x FANCM 相关的临床结果

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100 项与 RMI2 x RMI1 x FANCM 相关的转化医学

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0 项与 RMI2 x RMI1 x FANCM 相关的专利（医药）

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项与 RMI2 x RMI1 x FANCM 相关的文献（医药）

2024-01-01·Peptide and Peptide Mimicking Tools: Methods, Synthesis, Design & Applications

Fluorescence polarization assay for screening FANCM-RMI inhibitors to target the alternative lengthening of telomeres

Article

作者: Lau, Yu Heng ; Young, Reginald ; Alcock, Lisa J ; Sudhakar, Haritha Krishna

Alternative Lengthening of Telomeres (ALT) is a mechanism used by 10-15% of all cancers to achieve replicative immortality, bypassing the DNA damage checkpoint associated with short telomeres that leads to cellular senescence or apoptosis. ALT does not occur in non-cancerous cells, presenting a potential therapeutic window for cancers where this mechanism is active. Disrupting the FANCM-RMI interaction has emerged as a promising therapeutic strategy that induces synthetic ALT lethality in genetic studies on cancer cell lines. There are currently no chemical inhibitors reported in the literature, in part due to the lack of reliable biophysical or biochemical assays to screen for FANCM-RMI disruption. Here we describe the development of a robust competitive fluorescence polarization (FP) assay that quantifies target binding at the FANCM-RMI interface. The assay employs a labeled peptide tracer TMR-R_aMM2 derived from the native MM2 binding motif, which binds to recombinant RMI1-RMI2 and can be displaced by competitive inhibitors. We report the methods for recombinant production of RMI1-RMI2, design and evaluation of the tracer TMR-R_aMM2, along with unlabeled peptide inhibitor controls to enable ALT-targeted drug discovery.

2012-03-20·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome

1区 · 综合性期刊

Article

作者: Wang, Weidong ; Takata, Minoru ; Hoadley, Kelly A. ; Ling, Chen ; Keck, James L. ; Xue, Yutong

The RMI subcomplex (RMI1/RMI2) functions with the BLM helicase and topoisomerase IIIα in a complex called the “dissolvasome,” which separates double-Holliday junction DNA structures that can arise during DNA repair. This activity suppresses potentially harmful sister chromatid exchange (SCE) events in wild-type cells but not in cells derived from Bloom syndrome patients with inactivating BLM mutations. The RMI subcomplex also associates with FANCM, a component of the Fanconi anemia (FA) core complex that is important for repair of stalled DNA replication forks. The RMI/FANCM interface appears to help coordinate dissolvasome and FA core complex activities, but its precise role remains poorly understood. Here, we define the structure of the RMI/FANCM interface and investigate its roles in coordinating cellular DNA-repair activities. The X-ray crystal structure of the RMI core complex bound to a well-conserved peptide from FANCM shows that FANCM binds to both RMI proteins through a hydrophobic “knobs-into-holes” packing arrangement. The RMI/FANCM interface is shown to be critical for interaction between the components of the dissolvasome and the FA core complex. FANCM variants that substitute alanine for key interface residues strongly destabilize the complex in solution and lead to increased SCE levels in cells that are similar to those observed in blm - or fancm -deficient cells. This study provides a molecular view of the RMI/FANCM complex and highlights a key interface utilized in coordinating the activities of two critical eukaryotic DNA-damage repair machines.

Cell Discovery1区 · 生物学

Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks

1区 · 生物学

ArticleOA

作者: Mioko Ohzeki ; Dongyi Xu ; Minoru Takata ; Chen Ling ; Masamichi Ishiai ; Yongjiang Li ; Michael Seidman ; Weidong Wang ; Zhijiang Yan ; Jing Huang

AbstractThe recruitment of FANCM, a conserved DNA translocase and key component of several DNA repair protein complexes, to replication forks stalled by DNA interstrand crosslinks (ICLs) is a step upstream of the Fanconi anemia (FA) repair and replication traverse pathways of ICLs. However, detection of the FANCM recruitment has been technically challenging so that its mechanism remains exclusive. Here, we successfully observed recruitment of FANCM at stalled forks using a newly developed protocol. We report that the FANCM recruitment depends upon its intrinsic DNA translocase activity, and its DNA-binding partner FAAP24. Moreover, it is dependent on the replication checkpoint kinase, ATR; but is independent of the FA core and FANCD2–FANCI complexes, two essential components of the FA pathway, indicating that the FANCM recruitment occurs downstream of ATR but upstream of the FA pathway. Interestingly, the recruitment of FANCM requires its direct interaction with Bloom syndrome complex composed of BLM helicase, Topoisomerase 3α, RMI1 and RMI2; as well as the helicase activity of BLM. We further show that the FANCM–BLM complex interaction is critical for replication stress-induced FANCM hyperphosphorylation, for normal activation of the FA pathway in response to ICLs, and for efficient traverse of ICLs by the replication machinery. Epistasis studies demonstrate that FANCM and BLM work in the same pathway to promote replication traverse of ICLs. We conclude that FANCM and BLM complex work together at stalled forks to promote both FA repair and replication traverse pathways of ICLs.