A Histone-Fold Complex and FANCM Form a Conserved DNA-Remodeling Complex to Maintain Genome Stability

Yan, Zhijiang; Delannoy, Mathieu; Chen, Ling; Daee, Danielle L.; Osman, Fekret; Muniandy, Parameswary A.; Shen, Xi; Oostra, Anneke B.; Du, Huarui; Steltenpool, Jûrgen; Lin, Ti; Schuster, Beatrice; Décaillet, Chantal; Stasiak, Andrzej; Stasiak, Alicja Z.; Stone, Stacie; Hoatlin, Maureen E.; Schindler, Detlev; Woodcock, Christopher L.; Joenje, Hans; Sen, Ranjan; Winter, Johan P. de; Li, Lei; Seidman, Michael M.; Whitby, Matthew C.; Myung, Kyungjae; Constantinou, Angelos; Wang, Weidong

doi:10.1016/j.molcel.2010.01.039

Cited by 206 publications

(365 citation statements)

References 22 publications

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“…A theme that emerges from this work and previous studies is that depletion of proteins in either the BLM dissolvasome or the FA core complex, or disruption of protein interfaces that stabilize each complex or link the two, lead to similar increases in SCE levels ( Fig. 4 and (7,11,12,19,20). Taken together, these data suggest that the RMI/FANCM interface is critical in bridging the BLM dissolvasome and the FA core complexes and that proper association of these two complexes is vital in SCE suppression.…”

Section: Discussionsupporting

confidence: 52%

“…1F). FANCM could act to remodel the replication fork, possibly in coordination with BLM and Top3α (20)(21)(22)(23)(24). Furthermore, FANCM interacts with a large number of proteins that mediate many DNA-repair pathways.…”

Section: Discussionmentioning

confidence: 99%

“…For coimmunoprecipitation with FANCM, experiments were performed using anti-chicken FANCM antibody as described (20,30). Immunoblotting shows levels of FANCM and Top3α in whole-cell lysates from various DT40 cells (wild-type, rmi2 −∕− cells, and rmi2 −∕− cells complemented with human WT or Lys121Ala RMI2).…”

Section: Fitc Labeling Of Mm2 (F-mm2)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: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

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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“…CENP-S/MHF1 has a role in the resolution of DNA interstrand crosslinks and sister chromatid exchanges (SCEs) by the Fanconi Anemia complex. CENP-S is required for chromatin targeting and stability of the FANCM subcomplex, of which it is a member together with CENP-X/MHF2 (39,40). In DT40 cells, SCEs increased 3-4-fold when CENP-S/MHF1 was depleted (39,40).…”

Section: The Role Of Ccan Proteins In the Maintenance Of Kinetochorementioning

confidence: 99%

“…CENP-S is required for chromatin targeting and stability of the FANCM subcomplex, of which it is a member together with CENP-X/MHF2 (39,40). In DT40 cells, SCEs increased 3-4-fold when CENP-S/MHF1 was depleted (39,40). Thus, CENP-S involvement in centrochromatin stability may reflect a more general role in chromatin higher order structure across the cell cycle.…”

Section: The Role Of Ccan Proteins In the Maintenance Of Kinetochorementioning

confidence: 99%

Stepwise unfolding supports a subunit model for vertebrate kinetochores

Vargiu

Макаров

Allan

et al. 2017

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

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During cell division, interactions between microtubules and chromosomes are mediated by the kinetochore, a proteinaceous structure located at the primary constriction of chromosomes. In addition to the centromere histone centromere protein A (CENP-A), 15 other members of the constitutive centromere associated network (CCAN) participate in the formation of a chromatin-associated scaffold that supports kinetochore structure. We performed a targeted screen analyzing unfolded centrochromatin from CENP-depleted chromosomes. Our results revealed that CENP-C and CENP-S are critical for the stable folding of mitotic kinetochore chromatin. Multipeak fitting algorithms revealed the presence of an organized pattern of centrochromatin packing consistent with arrangement of CENP-A-containing nucleosomes into up to five chromatin "subunits"-each containing roughly 20-30 nucleosomes. These subunits could be either layers of a boustrophedon or small loops of centromeric chromatin.centromere | kinetochore | CENP-A | centrochromatin | boustrophedon

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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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A Histone-Fold Complex and FANCM Form a Conserved DNA-Remodeling Complex to Maintain Genome Stability

Cited by 206 publications

References 22 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

Stepwise unfolding supports a subunit model for vertebrate kinetochores

Mechanisms of DNA damage, repair, and mutagenesis

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