Guardians of the Genome: BRCA2 and Its Partners

Le, Hang Phuong; Heyer, Wolf‐Dietrich; Liu, Jie

doi:10.3390/genes12081229

Cited by 23 publications

(27 citation statements)

References 231 publications

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“…As another example of CRISPR-Select STATE , we determined that the BRCA2-T2722R pathogenic variant elicits accumulation of the DNA damage marker γH2AX in MCF10A cells (Extended Data Fig. 7a), consistent with the role of BRCA2 in genome maintenance 19 . Finally, we used CRISPR-Select STATE to dissect that the resistance mechanism of KRAS-12D toward AMG 510 in H358 cells involves the ability of KRAS-12D cells to proliferate in the presence of the drug (Extended Data Fig.…”

Section: Multiparametric Variant Analysis By Crispr-select State/spacesupporting

confidence: 55%

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Multiparametric and accurate functional analysis of genetic sequence variants using CRISPR-Select

Niu

Azevedo

et al. 2022

Nat Genet

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Determining the functional role of thousands of genetic sequence variants (mutations) associated with genetic diseases is a major challenge. Here we present clustered regularly interspaced short palindromic repeat (CRISPR)-SelectTIME, CRISPR-SelectSPACE and CRISPR-SelectSTATE, a set of flexible knock-in assays that introduce a genetic variant in a cell population and track its absolute frequencies relative to an internal, neutral control mutation as a function of time, space or a cell state measurable by flow cytometry. Phenotypically, CRISPR-Select can thereby determine, for example, pathogenicity, drug responsiveness/resistance or in vivo tumor promotion by a specific variant. Mechanistically, CRISPR-Select can dissect how the variant elicits the phenotype by causally linking the variant to motility/invasiveness or any cell state or biochemical process with a flow cytometry marker. The method is applicable to organoids, nontransformed or cancer cell lines. It is accurate, quantitative, fast and simple and works in single-well or 96-well higher throughput format. CRISPR-Select provides a versatile functional variant assay for research, diagnostics and drug development for genetic disorders.

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Section: Multiparametric Variant Analysis By Crispr-select State/spacesupporting

confidence: 55%

“…Finally, we tested the expert panel assessed pathogenic (loss-of-function) T2722R variant in the tumor suppressor gene BRCA2 (ref. 18 ), encoding a key factor for homologous recombination DNA repair, essential for proliferating cells 19 . Accordingly, CRISPR-Select TIME revealed a ~5-fold loss of cells with the BRCA2-T2722R variant over time (Fig.…”

mentioning

confidence: 99%

Multiparametric and accurate functional analysis of genetic sequence variants using CRISPR-Select

Niu

Azevedo

et al. 2022

Nat Genet

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“…BRCA2 is primarily a nuclear protein, and its subcellular localization is controlled by two NLSs and one nuclear export signal (NES). BRCA2 can recruit numerous regulatory proteins including RAD51, PALB2, BCCIP, EMSY and FANCD2 ( 8 , 9 ); this supports the hypothesis that BRCA2 is a multifunctional protein involved in numerous cellular pathways. In this article, we will briefly go through the role of BRCA2 in HR and present preliminary data obtained by differential RNA-seq analysis supporting the existence of new roles of BRCA2 in cell death regulation and metabolic reprogramming opening new avenues of investigations on the oncosuppressive role of BRCA2.…”

Section: Introductionmentioning

confidence: 57%

Yeast as a Model to Unravel New BRCA2 Functions in Cell Metabolism

et al. 2022

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Mutations in BRCA2 gene increase the risk for breast cancer and for other cancer types, including pancreatic and prostate cancer. Since its first identification as an oncosupressor in 1995, the best-characterized function of BRCA2 is in the repair of DNA double-strand breaks (DSBs) by homologous recombination. BRCA2 directly interacts with both RAD51 and single-stranded DNA, mediating loading of RAD51 recombinase to sites of single-stranded DNA. In the absence of an efficient homologous recombination pathway, DSBs accumulate resulting in genome instability, thus supporting tumorigenesis. Yet the precise mechanism by which BRCA2 exerts its tumor suppressor function remains unclear. BRCA2 has also been involved in other biological functions including protection of telomere integrity and stalled replication forks, cell cycle progression, transcriptional control and mitophagy. Recently, we and others have reported a role of BRCA2 in modulating cell death programs through a molecular mechanism conserved in yeast and mammals. Here we hypothesize that BRCA2 is a multifunctional protein which exerts specific functions depending on cell stress response pathway. Based on a differential RNA sequencing analysis carried out on yeast cells either growing or undergoing a regulated cell death process, either in the absence or in the presence of BRCA2, we suggest that BRCA2 causes central carbon metabolism reprogramming in response to death stimuli and encourage further investigation on the role of metabolic reprogramming in BRCA2 oncosuppressive function.

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“…In mammalian cells, BRCA2 is a large and intricate example of OB-fold regulation within a single, multi-functional protein Thorslund and West, 2007;Thorslund et al, 2010;Shahid et al, 2014). BRCA2 binds to multiple protein partners and to DNA, to mediate the repair of DNA double-strand breaks and inter-strand cross-links by RAD51-mediated homologous recombination (Dray et al, 2006;Saeki et al, 2006;Le et al, 2021).…”

Section: Frontiers Inmentioning

confidence: 99%

OB-fold Families of Genome Guardians: A Universal Theme Constructed From the Small β-barrel Building Block

Bianco

2022

Front. Mol. Biosci.

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The maintenance of genome stability requires the coordinated actions of multiple proteins and protein complexes, that are collectively known as genome guardians. Within this broadly defined family is a subset of proteins that contain oligonucleotide/oligosaccharide-binding folds (OB-fold). While OB-folds are widely associated with binding to single-stranded DNA this view is no longer an accurate depiction of how these domains are utilized. Instead, the core of the OB-fold is modified and adapted to facilitate binding to a variety of DNA substrates (both single- and double-stranded), phospholipids, and proteins, as well as enabling catalytic function to a multi-subunit complex. The flexibility accompanied by distinctive oligomerization states and quaternary structures enables OB-fold genome guardians to maintain the integrity of the genome via a myriad of complex and dynamic, protein-protein; protein-DNA, and protein-lipid interactions in both prokaryotes and eukaryotes.

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Guardians of the Genome: BRCA2 and Its Partners

Cited by 23 publications

References 231 publications

Multiparametric and accurate functional analysis of genetic sequence variants using CRISPR-Select

Multiparametric and accurate functional analysis of genetic sequence variants using CRISPR-Select

Yeast as a Model to Unravel New BRCA2 Functions in Cell Metabolism

OB-fold Families of Genome Guardians: A Universal Theme Constructed From the Small β-barrel Building Block

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