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Multiplexed assay of variant effect reveals residues of functional importance in the BRCA1 coiled-coil and serine cluster domains

ABSTRACT: Multiplexed assay of variant effect reveals residues of functional importance in the BRCA1 coiled-coil and serine cluster domains

PROVIDER: PRJNA994059 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25246300.fastq.gz	Fastqsanger.gz
	SRR25246301.fastq.gz	Fastqsanger.gz
	SRR25246302.fastq.gz	Fastqsanger.gz
	SRR25246303.fastq.gz	Fastqsanger.gz
	SRR25246304.fastq.gz	Fastqsanger.gz

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Multiplexed assay of variant effect reveals residues of functional importance in the BRCA1 coiled-coil and serine cluster domains

Project description:Delineating functionally normal variants from functionally abnormal variants in tumor suppressor proteins is critical for cancer surveillance, prognosis, and treatment options. BRCA1 is a protein that has many variants of uncertain significance which are not yet classified as functionally normal or abnormal. In vitro functional assays can be used to identify the functional impact of a variant when the variant has not yet been categorized through clinical observation. Here we employ a homology-directed repair (HDR) reporter assay to evaluate over 300 missense and nonsense BRCA1 variants between amino acid residues 1280 and 1576, which encompasses the coiled-coil and serine cluster domains. Functionally abnormal variants tended to cluster in residues known to interact with PALB2, which is critical for homology-directed repair. Multiplexed results were confirmed by singleton assay and by ClinVar database variant interpretations. Comparison of multiplexed results to designated benign or likely benign or pathogenic or likely pathogenic variants in the ClinVar database yielded 100% specificity and 100% sensitivity of the multiplexed assay. Clinicians can reference the results of this functional assay for help in guiding cancer treatment and surveillance options. These results are the first to evaluate this domain of BRCA1 using a multiplexed approach and indicate the importance of this domain in the DNA repair process.

2023-10-13 | GSE237142 | GEO

Expression data from HT-1080 cells incubated or not in the presence of laminin111 coiled-coiled recombinant fragment (rLCC111)

Project description:Laminins are large heterotrimeric cross-shaped extracellular matrix (ECM) glycoproteins with terminal globular domains and a coiled-coil region. We have produced for the first time a recombinant laminin coiled-coil domain and studied the transcriptional profile of cells incubated in coiled-coil-coated wells. Cells were incubated in 24w plates, onto coiled-coil-coated wells or control BSA-coated wells (one each), 24h

2011-10-11 | E-GEOD-32896 | biostudies-arrayexpress

A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair [CNV-seq]

Project description:The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSBs), which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered sequence variants of uncertain clinical significance (VUS). Using genetically engineered mice, we now show that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupting the interaction with PALB2 leads to embryonic lethality and loss of breast cancer suppression. Brca1 p.L1363P mammary tumors develop with a similar latency as Brca1-null tumors, but show different histopathological features and more stable DNA copy number profiles. Nevertheless, Brca1 p.L1363P mammary tumors are HRR-incompetent and responsive to cisplatin and PARP inhibition.

2022-02-01 | GSE182449 | GEO

A BRCA1 coiled-coil domain variant disrupting PALB2 interaction predisposes to mammary tumors with a targetable defect in homologous recombination repair [RNA-seq]

2022-02-01 | GSE182448 | GEO

Multiplexed assay of variant effect reveals residues of functional importance in the BRCA1 coiled-coil and serine cluster domains.

| S-EPMC10621863 | biostudies-literature

Expression data from HT-1080 cells incubated or not in the presence of laminin111 coiled-coiled recombinant fragment (rLCC111)

2011-10-12 | GSE32896 | GEO

A 36-base hairpin within lncRNA DRAIC interacts with the IKKα coiled-coil domain, weakening the IKK complex and inhibiting NF-kappaB activation

Project description:Long noncoding RNAs have diverse functions, but not enough is known about the molecular mechanisms underlying their cellular functions. The 1.7 kb long down-regulated non-coding RNA in cancers (DRAIC) slows tumor growth and inhibits the activation of the transcription factor NF-kappaB through interactions with IKK subunits. Starting with SHAPE-MaP-based structure-function studies of DRAIC we have now identified the minimal regions of DRAIC and IKK involved in the interactions and the anti-cancer function of DRAIC. A hairpin structure comprised of bases 705-722/741-758 (referred to as A+B) within DRAIC is responsible for inhibiting NF-kappaB activity. A+B binds specifically with the IKKα coiled-coil domain with a KD of ~1-5 nM. The coiled-coil domain of IKKα (the kinase subunit) and NEMO (the substrate recognition subunit,) mediate the dimerization of the subunits in the functional kinase complex. Consistent with its interaction with the coiled-coil domain of IKKα, A+B weakens the interaction between NEMO and the IKKα coiled-coil domain in an in vitro complex formation assay. The 36 nt A+B RNA was sufficient and necessary for DRAIC to inhibit tumor cell migration, invasion, and clonal growth in multiple cancer cell-lines. Therefore, this minimal hairpin fragment of the growth-suppressive DRAIC lncRNA inhibits NF-kappaB activation by interacting with high affinity with the coiled-coil domain of IKKα, weakening the interaction between the kinase subunit and the substrate recognition subunit of IKK, thereby inhibiting IB phosphorylation and NF-kappaB activation, and suppressing tumor phenotypes.

2025-07-01 | GSE279192 | GEO

Folding of cohesin's coiled coil is important for Scc2/4-induced association with chromosomes

Project description:Cohesin’s association with and translocation along chromosomal DNAs depend on an ATP hydrolysis cycle driving the association and subsequent release of DNA. This involves DNA being ‘clamped’ by Scc2 and ATP-dependent engagement of cohesin’s Smc1 and Smc3 head domains. Scc2’s replacement by Pds5 abrogates cohesin’s ATPase and has an important role in halting DNA loop extrusion. The ATPase domains of all SMC proteins are separated from their hinge dimerisation domains by 50 nm long coiled coils, which have been observed to zip up along their entire length and fold around an elbow, thereby greatly shortening the distance between hinges and ATPase heads. Whether folding exists in vivo or has any physiological importance is not known. We present here a cryo-EM structure of the apo form of cohesin that reveals the structure of folded and zipped up coils in unprecedented detail and shows that Scc2 can associate with Smc1’s ATPase head even when it is fully disengaged from that of Smc3. Using cysteine-specific cross-linking, we show that cohesin’s coiled coils are frequently folded in vivo, including when cohesin holds sister chromatids together. Moreover, we describe a mutation (SMC1D588Y) within Smc1’s hinge that alters how Scc2 and Pds5 interact with Smc1’s hinge and that enables Scc2 to support loading in the absence of its normal partner Scc4. The mutant phenotype of loading without Scc4 is only explicable if loading depends on an association between Scc2/4 and cohesin’s hinge, which in turn requires coiled coil folding.

2021-07-21 | GSE167318 | GEO

Effects of depletion of Rho-associated, coiled-coil-containing protein kinase 2 in the kidney medullary tussue of murine model.

Project description:Rho and its effector Rho-associated, coiled-coil–containing protein kinase 2 (ROCK2) play crucial roles in a variety of cellular functions, such as cell adhesion and cytoskeletal rearrangement . We here investigated the role of ROCK2 in the kidney medullary tissue using tubular specific ROCK2 knockout mice.

2024-07-01 | GSE246069 | GEO

Identification of the coiled-coil domain as an essential element of MBD3 for preserving lineage commitment potential of ESCs

Project description:As one of approaches for elucidating the molecular bases which define the difference for counteracting defect of Mbd3-knockout ESCs between MBD3a mutant lacking MBD domain and that lacking coiled-coil domain, we explored the possibility that these two mutants are different in their ability to recruit PRC2 complex in close vicinity by ChIP-sequence analyses.

2019-06-25 | GSE102643 | GEO

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