更新于：2024-11-01

RMI2

更新于：2024-11-01

基本信息

别名

BLAP18、BLM-associated protein of 18 kDa、C16orf75

+ [5]

简介

Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates. It is required to regulate sister chromatid segregation and to limit DNA crossover. Essential for the stability, localization, and function of BLM, TOP3A, and complexes containing BLM. In the RMI complex, it is required to target BLM to chromatin and stress-induced nuclear foci and mitotic phosphorylation of BLM.

关联

项与 RMI2 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 相关的临床结果

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100 项与 RMI2 相关的转化医学

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0 项与 RMI2 相关的专利（医药）

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项与 RMI2 相关的文献（医药）

2024-03-01·Journal of Crohn's and Colitis

Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes

Article

作者: Zheng, Tenghao ; Vigren, Lina ; Almer, Sven ; Guagnozzi, Danila ; Iglesias, Eva ; Mellander, Marie-Rose ; Bresso, Francesca ; Marsal, Sara ; Colombel, Jean-Frederic ; Ohlsson, Bodil ; Miehlke, Stephan ; Pierik, Marieke ; Piqueras, Marta ; Khalili, Hamed ; Ferrer, Carmen ; Ludvigsson, Jonas F ; Janczewska, Izabella ; Weersma, Rinse K ; Liu, Xingrong ; Halfvarson, Jonas ; Peter, Inga ; Julià, Antonio ; Madisch, Ahmed ; Busquets, David ; Bujanda, Luis ; Escudero-Hernández, Celia ; Chen, Ye ; Sjöberg, Klas ; Lieb, Wolfgang ; D’Amato, Mauro ; Franke, Andre ; Münch, Andreas ; Jonkers, Daisy ; Esteve, Maria ; Roda, Giulia ; Fernández-Bañares, Fernando ; Verhaegh, Bas ; Bonfiglio, Ferdinando ; Kupčinskas, Juozas ; Lucendo, Alfredo J ; Pardi, Darrell ; Zabana, Yamile ; Camargo Tavares, Leticia

AbstractBackground and AimsMicroscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies.MethodsWe conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied.ResultsWe detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC.ConclusionOur results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

2024-02-01·Molecular Cell

BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution

Article

作者: Bannister, Julius ; Jones, Samuel E ; Tsukada, Kaima ; Fawkes, Matthew ; Blackford, Andrew N ; Kessler, Benedikt M ; Fischer, Roman ; Vendrell, Iolanda ; Chapman, J Ross ; Durin, Mary-Anne

The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1, and RMI2 to form the BTR complex, which dissolves double Holliday junctions and DNA replication intermediates to promote sister chromatid disjunction before cell division. In its absence, structure-specific nucleases like the SMX complex (comprising SLX1-SLX4, MUS81-EME1, and XPF-ERCC1) can cleave joint DNA molecules instead, but cells deficient in both BTR and SMX are not viable. Here, we identify a negative genetic interaction between BLM loss and deficiency in the BRCA1-BARD1 tumor suppressor complex. We show that this is due to a previously overlooked role for BARD1 in recruiting SLX4 to resolve DNA intermediates left unprocessed by BLM in the preceding interphase. Consequently, cells with defective BLM and BRCA1-BARD1 accumulate catastrophic levels of chromosome breakage and micronucleation, leading to cell death. Thus, we reveal mechanistic insights into SLX4 recruitment to DNA lesions, with potential clinical implications for treating BRCA1-deficient tumors.

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.