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Scott Keeney
Memorial Sloan Kettering Cancer Center
Homologous recombinationMeiosisSpo11GeneticsBiology
161Publications
53H-index
11.2kCitations
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Publications 157
Newest
#1Anjali Gupta Hinch (University of Oxford)H-Index: 5
#2Philipp W. Becker (University of Oxford)H-Index: 3
Last. Benjamin J. Davies (University of Oxford)H-Index: 26
view all 11 authors...
Summary Meiotic recombination proceeds via binding of RPA, RAD51, and DMC1 to single-stranded DNA (ssDNA) substrates created after formation of programmed DNA double-strand breaks. Here we report high-resolution in vivo maps of RPA and RAD51 in meiosis, mapping their binding locations and lifespans to individual homologous chromosomes using a genetically engineered hybrid mouse. Together with high-resolution microscopy and DMC1 binding maps, we show that DMC1 and RAD51 have distinct spatial loca...
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#1Agnieszka Lukaszewicz (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 1
#2Julian Lange (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 18
Last. Maria Jasin (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 64
view all 4 authors...
Numerous DNA double-strand breaks (DSBs) arise genome-wide during meiosis to ensure recombination between homologous chromosomes, which is required for gamete formation. The ATM kinase plays a central role in controlling both the number and position of DSBs, but the consequences of deregulated DSB formation have not been explored. Here we discovered that an unanticipated type of DNA deletion arises at meiotic recombination hotspots in the absence of ATM. Deletions form via joining of ends from t...
Source
#1Shintaro Yamada (Kyoto University)H-Index: 5
#2Anjali Gupta Hinch (University of Oxford)H-Index: 5
Last. Scott Keeney (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 53
view all 6 authors...
Exonucleolytic resection, critical to repair double-strand breaks (DSBs) by recombination, is not well understood, particularly in mammalian meiosis. Here, we define structures of resected DSBs in mouse spermatocytes genome-wide at nucleotide resolution. Resection tracts averaged 1100 nt, but with substantial fine-scale heterogeneity at individual hot spots. Surprisingly, EXO1 is not the major 5' --> 3' exonuclease, but the DSB-responsive kinase ATM proved a key regulator of both initiation and ...
6 CitationsSource
#1Laurent Acquaviva (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 3
#2Michiel Boekhout (UU: Utrecht University)H-Index: 3
Last. Maria Jasin (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 64
view all 11 authors...
Sex chromosomes in males of most eutherian mammals share only a small homologous segment, the pseudoautosomal region (PAR), in which the formation of double-strand breaks (DSBs), pairing and crossing over must occur for correct meiotic segregation1,2. How cells ensure that recombination occurs in the PAR is unknown. Here we present a dynamic ultrastructure of the PAR and identify controlling cis- and trans-acting factors that make the PAR the hottest segment for DSB formation in the male mouse g...
4 CitationsSource
#1X. Mu (MSK: Memorial Sloan Kettering Cancer Center)
#1Xiaojing Mu (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 1
Last. S. Keeney
view all 4 authors...
The number of DNA double-strand breaks (DSBs) initiating meiotic recombination is elevated in Saccharomyces cerevisiae mutants that are globally defective in forming crossovers and synaptonemal complex (SC), a protein scaffold juxtaposing aligned homologous chromosomes. These mutants thus appear to lack a negative feedback loop that inhibits DSB formation when homologs engage one another. This feedback is predicted to be chromosome autonomous, but this has not been tested in yeast. Moreover, wha...
1 CitationsSource
#1Cynthia Petrillo (Université Paris-Saclay)
#2Vilma Barroca (Université Paris-Saclay)
Last. Devanshi Jain (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 4
view all 8 authors...
Recombination is crucial for chromosome pairing and segregation during meiosis. SPATA22, along with its direct binding partner and functional collaborator, MEIOB, is essential for the proper repair of double-strand breaks (DSBs) during meiotic recombination. Here, we describe a novel point-mutated allele (shani) of mouse Spata22 that we isolated in a forward genetic screen. shani mutant mice phenocopy Spata22-null and Meiob-null mice: mutant cells appear to form DSBs and initiate meiotic recombi...
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#1Hajime Murakami (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 8
#2Isabel Lam (Brigham and Women's Hospital)H-Index: 1
Last. Scott KeeneyH-Index: 53
view all 6 authors...
In most species, homologous chromosomes must recombine in order to segregate accurately during meiosis1. Because small chromosomes would be at risk of missegregation if recombination were randomly distributed, the double-strand breaks (DSBs) that initiate recombination are not located arbitrarily2. How the nonrandomness of DSB distributions is controlled is not understood, although several pathways are known to regulate the timing, location and number of DSBs. Meiotic DSBs are generated by Spo11...
2 CitationsSource
#1Shaun E. Peterson (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 7
#2Scott Keeney (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 53
Last. Maria Jasin (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 16
view all 3 authors...
Summary Crossover recombination is critical for meiotic chromosome segregation, but how mammalian crossing over is accomplished is poorly understood. Here, we illuminate how strands exchange during meiotic recombination in male mice by analyzing patterns of heteroduplex DNA in recombinant molecules preserved by the mismatch correction deficiency of Msh2–/– mutants. Surprisingly, MSH2-dependent recombination suppression was not evident. However, a substantial fraction of crossover products retain...
1 CitationsSource
#1Corentin Claeys Bouuaert (UCL: Université catholique de Louvain)H-Index: 9
#2Stephen Pu (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 2
Last. Scott Keeney (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 53
view all 5 authors...
Formation of meiotic DNA double-strand breaks (DSBs) by Spo11 is tightly regulated and tied to chromosome structure, but the higher-order assemblies that execute and control DNA breakage are poorly understood. We address this question through molecular characterization of Saccharomyces cerevisiae RMM proteins (Rec114, Mei4 and Mer2)-essential, conserved components of the DSB machinery. Each subcomplex of Rec114-Mei4 (2:1 heterotrimer) or Mer2 (homotetrameric coiled coil) is monodisperse in solut...
2 CitationsSource
#1Corentin Claeys Bouuaert (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 9
#2Sam E. Tischfield (Cornell University)H-Index: 6
Last. Scott Keeney (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 53
view all 7 authors...
Spo11, which makes DNA double-strand breaks (DSBs) essential for meiotic recombination, is poorly understood mechanistically because it has been recalcitrant to biochemical study. Here, we provide a molecular analysis of S. cerevisiae Spo11 purified with partners Rec102, Rec104 and Ski8. Rec102 and Rec104 jointly resemble the B subunit of archaeal Topoisomerase VI, with Rec104 similar to a GHKL domain but without conserved ATPase motifs. Unexpectedly, the Spo11 complex is monomeric (1:1:1:1 stoi...
3 CitationsSource
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