FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4313365796> ?p ?o ?g. }

• W4313365796 abstract "Abstract Mutations in the breast cancer susceptibility gene, BRCA2, greatly increase an individual’s lifetime risk of developing breast and ovarian cancers. BRCA2 suppresses tumor formation by potentiating DNA repair via homologous recombination. Central to recombination is the assembly of a RAD51 nucleoprotein filament, which forms on single-stranded DNA (ssDNA) generated at or near the site of chromosomal damage. However, Replication Protein-A (RPA) rapidly binds to and continuously sequesters this ssDNA, imposing a kinetic barrier to RAD51 filament assembly that suppresses unregulated recombination. Recombination mediator proteins––of which BRCA2 is the defining member in humans ––alleviate this kinetic barrier to catalyze RAD51 filament formation. We combined microfluidics, microscopy, and micromanipulation to directly measure both the binding of full-length BRCA2 to––and the assembly of RAD51 filaments on––a region of RPA-coated ssDNA within individual DNA molecules designed to mimic a resected DNA lesion common in replication-coupled recombinational repair. We demonstrate that a dimer of RAD51 is minimally required for spontaneous nucleation; however, growth self-terminates below the diffraction limit. BRCA2 accelerates nucleation of RAD51 to a rate that approaches the rapid association of RAD51 to naked ssDNA, thereby overcoming the kinetic block imposed by RPA. Furthermore, BRCA2 eliminates the need for the rate-limiting nucleation of RAD51 by chaperoning a short pre-assembled RAD51 filament onto the ssDNA complexed with RPA. Therefore, BRCA2 regulates recombination by initiating RAD51 filament formation. Significance Despite decades of genetic and cell biological studies, mechanistic biochemical analyses of human BRCA2 function in recombinational DNA repair have only been possible since the purification of full-length BRCA2. These mechanistic studies crucially inform with respect to the molecular function of BRCA2 in genome maintenance. Here, we use single-molecule methods to visualize the assembly of RAD51 on individual RPA-coated ssDNA molecules and to see how this process is regulated by the tumor suppressor protein, BRCA2. We show that BRCA2 serves as a chaperone to nucleate RAD51 and deliver it to RPA-coated ssDNA. This work advances understanding of the molecular functions of BRCA2 and, consequently, the molecular etiology of breast cancer in an important way." @default.
• W4313365796 created "2023-01-06" @default.
• W4313365796 creator A5002209510 @default.
• W4313365796 creator A5024559124 @default.
• W4313365796 creator A5032365839 @default.
• W4313365796 creator A5058811980 @default.
• W4313365796 creator A5085802137 @default.
• W4313365796 date "2022-12-29" @default.
• W4313365796 modified "2023-09-30" @default.
• W4313365796 title "BRCA2 chaperones RAD51 to single molecules of RPA-coated ssDNA" @default.
• W4313365796 cites W1521943738 @default.
• W4313365796 cites W1567965727 @default.
• W4313365796 cites W1961774825 @default.
• W4313365796 cites W1965421709 @default.
• W4313365796 cites W1968099812 @default.
• W4313365796 cites W1969839636 @default.
• W4313365796 cites W1980455934 @default.
• W4313365796 cites W1987058955 @default.
• W4313365796 cites W1989140691 @default.
• W4313365796 cites W2005548481 @default.
• W4313365796 cites W2009309406 @default.
• W4313365796 cites W2014140511 @default.
• W4313365796 cites W2021955395 @default.
• W4313365796 cites W2030093162 @default.
• W4313365796 cites W2035301796 @default.
• W4313365796 cites W2047746027 @default.
• W4313365796 cites W2049729115 @default.
• W4313365796 cites W2050537059 @default.
• W4313365796 cites W2055761018 @default.
• W4313365796 cites W2061151099 @default.
• W4313365796 cites W2084034209 @default.
• W4313365796 cites W2085544302 @default.
• W4313365796 cites W2091350790 @default.
• W4313365796 cites W2098812676 @default.
• W4313365796 cites W2104003823 @default.
• W4313365796 cites W2116192803 @default.
• W4313365796 cites W2134536765 @default.
• W4313365796 cites W2136989353 @default.
• W4313365796 cites W2140036600 @default.
• W4313365796 cites W2141989464 @default.
• W4313365796 cites W2149326807 @default.
• W4313365796 cites W2153579158 @default.
• W4313365796 cites W2156003892 @default.
• W4313365796 cites W2170509903 @default.
• W4313365796 cites W2173561323 @default.
• W4313365796 cites W2186009265 @default.
• W4313365796 cites W2339469992 @default.
• W4313365796 cites W2345476987 @default.
• W4313365796 doi "https://doi.org/10.1101/2022.12.28.522061" @default.
• W4313365796 hasPublicationYear "2022" @default.
• W4313365796 type Work @default.
• W4313365796 citedByCount "0" @default.
• W4313365796 crossrefType "posted-content" @default.
• W4313365796 hasAuthorship W4313365796A5002209510 @default.
• W4313365796 hasAuthorship W4313365796A5024559124 @default.
• W4313365796 hasAuthorship W4313365796A5032365839 @default.
• W4313365796 hasAuthorship W4313365796A5058811980 @default.
• W4313365796 hasAuthorship W4313365796A5085802137 @default.
• W4313365796 hasBestOaLocation W43133657961 @default.
• W4313365796 hasConcept C102744134 @default.
• W4313365796 hasConcept C104317684 @default.
• W4313365796 hasConcept C113271649 @default.
• W4313365796 hasConcept C12554922 @default.
• W4313365796 hasConcept C134935766 @default.
• W4313365796 hasConcept C13514818 @default.
• W4313365796 hasConcept C14228908 @default.
• W4313365796 hasConcept C143425029 @default.
• W4313365796 hasConcept C153911025 @default.
• W4313365796 hasConcept C185592680 @default.
• W4313365796 hasConcept C2779012473 @default.
• W4313365796 hasConcept C2909462720 @default.
• W4313365796 hasConcept C501734568 @default.
• W4313365796 hasConcept C54355233 @default.
• W4313365796 hasConcept C552990157 @default.
• W4313365796 hasConcept C86339819 @default.
• W4313365796 hasConcept C86803240 @default.
• W4313365796 hasConcept C94966510 @default.
• W4313365796 hasConcept C95444343 @default.
• W4313365796 hasConceptScore W4313365796C102744134 @default.
• W4313365796 hasConceptScore W4313365796C104317684 @default.
• W4313365796 hasConceptScore W4313365796C113271649 @default.
• W4313365796 hasConceptScore W4313365796C12554922 @default.
• W4313365796 hasConceptScore W4313365796C134935766 @default.
• W4313365796 hasConceptScore W4313365796C13514818 @default.
• W4313365796 hasConceptScore W4313365796C14228908 @default.
• W4313365796 hasConceptScore W4313365796C143425029 @default.
• W4313365796 hasConceptScore W4313365796C153911025 @default.
• W4313365796 hasConceptScore W4313365796C185592680 @default.
• W4313365796 hasConceptScore W4313365796C2779012473 @default.
• W4313365796 hasConceptScore W4313365796C2909462720 @default.
• W4313365796 hasConceptScore W4313365796C501734568 @default.
• W4313365796 hasConceptScore W4313365796C54355233 @default.
• W4313365796 hasConceptScore W4313365796C552990157 @default.
• W4313365796 hasConceptScore W4313365796C86339819 @default.
• W4313365796 hasConceptScore W4313365796C86803240 @default.
• W4313365796 hasConceptScore W4313365796C94966510 @default.
• W4313365796 hasConceptScore W4313365796C95444343 @default.
• W4313365796 hasLocation W43133657961 @default.
• W4313365796 hasLocation W43133657962 @default.
• W4313365796 hasOpenAccess W4313365796 @default.

• next