Sue Jinks-Robertson

Overview:

My research focuses on the regulation of genetic stability and primarily uses budding yeast (Saccharomyces cerevisiae) as a model genetic system.  The two primary research goals in the budding yeast system are (1) defining molecular structures and mechanisms of mitotic recombination intermediates and (2) understanding how and why transcription destabilizes the underlying DNA template.  We also have initiated studies of mutagenesis in the pathogenic fungus Cryptococcus neoformans.  We have found that a shift to the human body temperature mobilizes transposable elements, and suggest that this promotes rapid adaptation to the harsh host environment.  

Positions:

James B. Duke Distinguished Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Vice-Chair in the Department of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1983

University of Wisconsin - Madison

Grants:

Temperature-dependent transposon mobilization in Cryptococcus neoformans

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Regulation of mitotic genome stability in yeast.

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

What Happens at a Double Strand Break: Investigating the Role of DNA End Structure in Homologous Recombination

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Investigating the origin of spontaneous mitotic homologous recombination in Saccharomyces cerevisiae

Administered By
Molecular Genetics and Microbiology
Awarded By
American Heart Association
Role
Principal Investigator
Start Date
End Date

Mitotic recombination mechanisms in yeast

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Genome-wide analysis of heat stress-stimulated transposon mobility in the human fungal pathogen <i>Cryptococcus deneoformans</i>

Authors
Gusa, A; Yadav, V; Roth, C; Williams, JD; Shouse, EM; Magwene, P; Heitman, J; Jinks-Robertson, S
MLA Citation
Gusa, Asiya, et al. “Genome-wide analysis of heat stress-stimulated transposon mobility in the human fungal pathogen Cryptococcus deneoformans.” Cold Spring Harbor Laboratory, 10 June 2022. Manual, doi:10.1101/2022.06.10.495668.
URI
https://scholars.duke.edu/individual/pub1523722
Source
manual
Published Date
DOI
10.1101/2022.06.10.495668

Recurrent mutations in topoisomerase IIα cause a previously undescribed mutator phenotype in human cancers.

Topoisomerases nick and reseal DNA to relieve torsional stress associated with transcription and replication and to resolve structures such as knots and catenanes. Stabilization of the yeast Top2 cleavage intermediates is mutagenic in yeast, but whether this extends to higher eukaryotes is less clear. Chemotherapeutic topoisomerase poisons also elevate cleavage, resulting in mutagenesis. Here, we describe p.K743N mutations in human topoisomerase hTOP2α and link them to a previously undescribed mutator phenotype in cancer. Overexpression of the orthologous mutant protein in yeast generated a characteristic pattern of 2- to 4-base pair (bp) duplications resembling those in tumors with p.K743N. Using mutant strains and biochemical analysis, we determined the genetic requirements of this mutagenic process and showed that it results from trapping of the mutant yeast yTop2 cleavage complex. In addition to 2- to 4-bp duplications, hTOP2α p.K743N is also associated with deletions that are absent in yeast. We call the combined pattern of duplications and deletions ID_TOP2α. All seven tumors carrying the hTOP2α p.K743N mutation showed ID_TOP2α, while it was absent from all other tumors examined (n = 12,269). Each tumor with the ID_TOP2α signature had indels in several known cancer genes, which included frameshift mutations in tumor suppressors PTEN and TP53 and an activating insertion in BRAF. Sequence motifs found at ID_TOP2α mutations were present at 80% of indels in cancer-driver genes, suggesting that ID_TOP2α mutagenesis may contribute to tumorigenesis. The results reported here shed further light on the role of topoisomerase II in genome instability.
Authors
Boot, A; Liu, M; Stantial, N; Shah, V; Yu, W; Nitiss, KC; Nitiss, JL; Jinks-Robertson, S; Rozen, SG
MLA Citation
Boot, Arnoud, et al. “Recurrent mutations in topoisomerase IIα cause a previously undescribed mutator phenotype in human cancers.Proc Natl Acad Sci U S A, vol. 119, no. 4, Jan. 2022. Pubmed, doi:10.1073/pnas.2114024119.
URI
https://scholars.duke.edu/individual/pub1506950
PMID
35058360
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
119
Published Date
DOI
10.1073/pnas.2114024119

Mutagenic repair of a ZFN-induced double-strand break in yeast: Effects of cleavage site sequence and spacer size.

Double-strand breaks are repaired by error-free homologous recombination or by relatively error-prone pathways that directly join broken ends. Both types of repair have been extensively studied in Saccharomyces cerevisiae using enzymes HO or I-SceI, which create breaks with 4-nt 3' overhangs. In the current study, a galactose-regulated zinc-finger nuclease (ZFN) designed to cleave the Drosophila rosy locus was used to generate breaks with 4-nt 5' overhangs at out-of-frame cleavage sites inserted into the yeast LYS2 gene. Mutagenic repair was examined following selection of prototrophs on lysine-deficient medium containing galactose or surviving colonies on galactose-containing rich medium. Following cleavage of the original rosy spacer (ACGAAT), most Lys+ colonies contained 1- or 4-bp insertions at the cleavage site while most survivors had either a 2-bp insertion or a large deletion. Small insertions reflected nonhomologous end joining (NHEJ) and large deletions were the product of microhomology-mediated end joining (MMEJ). Changing the original ACGAAT spacer to either AGCAAT, ACGCGT or CTATTA altered the molecular features of NHEJ events as well as their frequency relative to MMEJ. Altering the optimal 6-bp spacer size between the zinc-finger protein binding sites to 5 bp or 7 bp eliminated the effect of continuous ZFN expression on survival, but Lys+ prototrophs were still generated. Analysis of Lys+ revertants after cleavage of the 5-bp spacer indicated that both the position and spacing of ZFN-generated nicks were variable. Results provide insight into effects of overhang sequence on mutagenic outcomes and demonstrate ZFN cleavage of 5- or 7-bp spacers in vivo.
Authors
MLA Citation
Shaltz, Samantha, and Sue Jinks-Robertson. “Mutagenic repair of a ZFN-induced double-strand break in yeast: Effects of cleavage site sequence and spacer size.Dna Repair (Amst), vol. 108, Dec. 2021, p. 103228. Pubmed, doi:10.1016/j.dnarep.2021.103228.
URI
https://scholars.duke.edu/individual/pub1497143
PMID
34601383
Source
pubmed
Published In
Dna Repair (Amst)
Volume
108
Published Date
Start Page
103228
DOI
10.1016/j.dnarep.2021.103228

Mitotic recombination in yeast: what we know and what we don't know.

Saccharomyces cerevisiae is at the forefront of defining the major recombination mechanisms/models that repair targeted double-strand breaks during mitosis. Each of these models predicts specific molecular intermediates as well as genetic outcomes. Recent use of single-nucleotide polymorphisms to track the exchange of sequences in recombination products has provided an unprecedented level of detail about the corresponding intermediates and the extents to which different mechanisms are utilized. This approach also has revealed complexities that are not predicted by canonical models, suggesting that modifications to these models are needed. Current data are consistent with the initiation of most inter-homolog spontaneous mitotic recombination events by a double-strand break. In addition, the sister chromatid is preferred over the homolog as a repair template.
MLA Citation
Jinks-Robertson, Sue, and Thomas D. Petes. “Mitotic recombination in yeast: what we know and what we don't know.Curr Opin Genet Dev, vol. 71, Dec. 2021, pp. 78–85. Pubmed, doi:10.1016/j.gde.2021.07.002.
URI
https://scholars.duke.edu/individual/pub1489698
PMID
34311384
Source
pubmed
Published In
Curr Opin Genet Dev
Volume
71
Published Date
Start Page
78
End Page
85
DOI
10.1016/j.gde.2021.07.002

High-Throughput Analysis of Heteroduplex DNA in Mitotic Recombination Products.

Mitotic double-strand breaks (DSBs) are repaired by recombination with a homologous donor duplex. This process involves the exchange of single DNA strands between the broken molecule and the repair template, giving rise to regions of heteroduplex DNA (hetDNA). The creation of a defined DSB coupled with the use of a sequence-diverged repair template allows the fine-structure mapping of hetDNA through the sequencing of recombination products. A high-throughput method is described that capitalizes on the single-molecule real-time (SMRT) sequencing technology developed by PacBio. This method allows simultaneous analysis of the hetDNA contained within hundreds of recombination products.
Authors
Gamble, D; Hum, YF; Jinks-Robertson, S
MLA Citation
Gamble, Dionna, et al. High-Throughput Analysis of Heteroduplex DNA in Mitotic Recombination Products. Vol. 2153, 2021, pp. 503–19. Pubmed, doi:10.1007/978-1-0716-0644-5_34.
URI
https://scholars.duke.edu/individual/pub1460170
PMID
32840801
Source
pubmed
Volume
2153
Published Date
Start Page
503
End Page
519
DOI
10.1007/978-1-0716-0644-5_34

Research Areas:

DNA Repair
Gene Conversion
Genetic recombination
Insertional mutagenesis
Mutagenesis
Recombinational DNA Repair
Transcription