RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability

Xu, Dongyi; Guo, Rong; Sobeck, Alexandra; Bachrati, Csanád Z.; Yang, Jay; Enomoto, Takemi; Brown, Grant W.; Hoatlin, Maureen E.; Hickson, Ian D.; Wang, Weidong

doi:10.1101/gad.1708608

Cited by 186 publications

(304 citation statements)

References 43 publications

(65 reference statements)

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“…1D). Top3α and RMI1 coimmunoprecipitated with both Flag-tagged RMI2 proteins as has been observed previously (7,12). These data indicate that the Lys121Ala sequence change in RMI2 specifically abrogates binding to FANCM and identify a role for RMI2 in FANCM binding.…”

Section: Resultssupporting

confidence: 84%

“…Previous studies have shown that the C-terminal OB domain of RMI1 (RMI1 OB2) interacts both with the MM2 region of FANCM and with RMI2 ( Fig. 1A) (7,8,12,13,17). We have confirmed the RMI/FANCM interaction in vitro by demonstrating that a glutathione S-transferase (GST)-MM2 fusion protein forms a complex with the RMI core complex (RMI1 OB2 in complex with RMI2) using analytical size-exclusion chromatography (Fig.…”

Section: Resultssupporting

confidence: 68%

“…Previous results have shown that the RMI2 variant Lys121Ala exhibits no defect in coimmunoprecipitation with other members of the BLM dissolvasome but shows increases in cellular SCE levels (7,12). We therefore tested a possible role for Lys121 from RMI2 in MM2 binding using the FP assay.…”

Section: Resultsmentioning

confidence: 99%

“…BS cells display elevated levels of SCEs, which is consistent with the proposed role for the BLM helicase in the nonrecombinogenic repair of doubleHolliday junction (dHJ) DNA structures that can arise during repair. To catalyze this activity, BLM functions within a complex called the "dissolvasome" that also includes topoisomerase IIIα (Top3α) and the RecQ-mediated genome instability, or RMI, subcomplex (RMI1/RMI2 heterodimer) (7)(8)(9)(10)(11)(12)(13). The dissolvasome is thought to drive HJ branch migration (catalyzed by BLM) and DNA cleavage of the resulting hemi-catenated DNA (catalyzed by Top3α) in a reaction called "dissolution" (14).…”

mentioning

confidence: 99%

“…The dissolvasome is thought to drive HJ branch migration (catalyzed by BLM) and DNA cleavage of the resulting hemi-catenated DNA (catalyzed by Top3α) in a reaction called "dissolution" (14). The RMI subcomplex stimulates these activities and stabilizes the dissolvasome (7,8,10).…”

mentioning

confidence: 99%

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

Hoadley

Xue

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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 "knobsinto-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.

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Section: Resultssupporting

confidence: 84%

Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Hoadley

Xue

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Role of homologous recombination in DNA interstrand crosslink repair

Hinz

2010

Environ and Mol Mutagen

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Homologous recombination repair (HRR) encompasses mechanisms that employ homologous DNA sequences as templates for repair or tolerance of a wide range of DNA lesions that inhibit DNA replication in S phase. Arguably the most imposing of these DNA lesions is that of the interstrand crosslink (ICL), consisting of a covalently attached chemical bridge between opposing DNA strands. ICL repair requires the coordinated activities of HRR and a number of proteins from other DNA repair and damage response systems, including nucleotide excision repair, base excision repair, mismatch repair, and translesion DNA synthesis (TLS). Interestingly, different organisms favor alternative methods of HRR in the ICL repair process. E. coli perform ICL repair using a homology-driven damage bypass mechanism analogous to daughter strand gap repair. Eukaryotes from yeast to humans initiate ICL repair primarily during DNA replication, relying on HRR activity to restart broken replication forks associated with double-strand break intermediates induced by nucleolytic activities of other excision repair factors. Higher eukaryotes also employ several additional factors, including members of the Fanconi anemia damage-response network, which further promote replication-associated ICL repair through the activation and coordination of various DNA excision repair, TLS, and HRR proteins. This review focuses on the proteins and general mechanisms of HRR associated with ICL repair in different model organisms.

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Mechanisms of DNA damage, repair, and mutagenesis

Chatterjee

Walker

2017

Environ and Mol Mutagen

1,425

995

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Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue.

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RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability

Abstract: [Keywords: Bloom syndrome; BLM; BLAP75; RMI1; RMI2; Topoisomerase 3␣] Supplemental material is available at http://www.genesdev.org.

Cited by 186 publications

References 43 publications

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

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

Role of homologous recombination in DNA interstrand crosslink repair

Mechanisms of DNA damage, repair, and mutagenesis

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