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:

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 at 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

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

Publications:

Mitotic Recombination and Adaptive Genomic Changes in Human Pathogenic Fungi.

Genome rearrangements and ploidy alterations are important for adaptive change in the pathogenic fungal species Candida and Cryptococcus, which propagate primarily through clonal, asexual reproduction. These changes can occur during mitotic growth and lead to enhanced virulence, drug resistance, and persistence in chronic infections. Examples of microevolution during the course of infection were described in both human infections and mouse models. Recent discoveries defining the role of sexual, parasexual, and unisexual cycles in the evolution of these pathogenic fungi further expanded our understanding of the diversity found in and between species. During mitotic growth, damage to DNA in the form of double-strand breaks (DSBs) is repaired, and genome integrity is restored by the homologous recombination and non-homologous end-joining pathways. In addition to faithful repair, these pathways can introduce minor sequence alterations at the break site or lead to more extensive genetic alterations that include loss of heterozygosity, inversions, duplications, deletions, and translocations. In particular, the prevalence of repetitive sequences in fungal genomes provides opportunities for structural rearrangements to be generated by non-allelic (ectopic) recombination. In this review, we describe DSB repair mechanisms and the types of resulting genome alterations that were documented in the model yeast Saccharomyces cerevisiae. The relevance of similar recombination events to stress- and drug-related adaptations and in generating species diversity are discussed for the human fungal pathogens Candida albicans and Cryptococcus neoformans.
Authors
MLA Citation
Gusa, Asiya, and Sue Jinks-Robertson. “Mitotic Recombination and Adaptive Genomic Changes in Human Pathogenic Fungi.Genes (Basel), vol. 10, no. 11, Nov. 2019. Pubmed, doi:10.3390/genes10110901.
URI
https://scholars.duke.edu/individual/pub1421694
PMID
31703352
Source
pubmed
Published In
Genes
Volume
10
Published Date
DOI
10.3390/genes10110901

Deletions associated with stabilization of the Top1 cleavage complex in yeast are products of the nonhomologous end-joining pathway.

Topoisomerase I (Top1) resolves supercoils by nicking one DNA strand and facilitating religation after torsional stress has been relieved. During its reaction cycle, Top1 forms a covalent cleavage complex (Top1cc) with the nicked DNA, and this intermediate can be converted into a toxic double-strand break (DSB) during DNA replication. We previously reported that Top1cc trapping in yeast increases DSB-independent, short deletions at tandemly repeated sequences. In the current study, we report a type of DSB-dependent mutation associated with Top1cc stabilization: large deletions (median size, ∼100 bp) with little or no homology at deletion junctions. Genetic analyses demonstrated that Top1cc-dependent large deletions are products of the nonhomologous end-joining (NHEJ) pathway and require Top1cc removal from DNA ends. Furthermore, these events accumulated in quiescent cells, suggesting that the causative DSBs may arise outside the context of replication. We propose a model in which the ends of different, Top1-associated DSBs are joined via NHEJ, which results in deletion of the intervening sequence. These findings have important implications for understanding the mutagenic effects of chemotherapeutic drugs that stabilize the Top1cc.
Authors
MLA Citation
Cho, Jang-Eun, and Sue Jinks-Robertson. “Deletions associated with stabilization of the Top1 cleavage complex in yeast are products of the nonhomologous end-joining pathway.Proc Natl Acad Sci U S A, vol. 116, no. 45, Nov. 2019, pp. 22683–91. Pubmed, doi:10.1073/pnas.1914081116.
URI
https://scholars.duke.edu/individual/pub1421695
PMID
31636207
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
116
Published Date
Start Page
22683
End Page
22691
DOI
10.1073/pnas.1914081116

Role of the Srs2-Rad51 Interaction Domain in Crossover Control in Saccharomyces cerevisiae.

Saccharomyces cerevisiae Srs2, in addition to its well-documented antirecombination activity, has been proposed to play a role in promoting synthesis-dependent strand annealing (SDSA). Here we report the identification and characterization of an SRS2 mutant with a single amino acid substitution (srs2-F891A) that specifically affects the Srs2 pro-SDSA function. This residue is located within the Srs2-Rad51 interaction domain and embedded within a protein sequence resembling a BRC repeat motif. The srs2-F891A mutation leads to a complete loss of interaction with Rad51 as measured through yeast two-hybrid analysis and a partial loss of interaction as determined through protein pull-down assays with purified Srs2, Srs2-F891A, and Rad51 proteins. Even though previous work has shown that internal deletions of the Srs2-Rad51 interaction domain block Srs2 antirecombination activity in vitro, the Srs2-F891A mutant protein, despite its weakened interaction with Rad51, exhibits no measurable defect in antirecombination activity in vitro or in vivo Surprisingly, srs2-F891A shows a robust shift from noncrossover to crossover repair products in a plasmid-based gap repair assay, but not in an ectopic physical recombination assay. Our findings suggest that the Srs2 C-terminal Rad51 interaction domain is more complex than previously thought, containing multiple interaction sites with unique effects on Srs2 activity.
Authors
Jenkins, SS; Gore, S; Guo, X; Liu, J; Ede, C; Veaute, X; Jinks-Robertson, S; Kowalczykowski, SC; Heyer, W-D
MLA Citation
Jenkins, Shirin S., et al. “Role of the Srs2-Rad51 Interaction Domain in Crossover Control in Saccharomyces cerevisiae.Genetics, vol. 212, no. 4, Aug. 2019, pp. 1133–45. Pubmed, doi:10.1534/genetics.119.302337.
URI
https://scholars.duke.edu/individual/pub1388055
PMID
31142613
Source
pubmed
Published In
Genetics
Volume
212
Published Date
Start Page
1133
End Page
1145
DOI
10.1534/genetics.119.302337

Mismatch recognition and subsequent processing have distinct effects on mitotic recombination intermediates and outcomes in yeast.

The post-replicative mismatch repair (MMR) system has anti-recombination activity that limits interactions between diverged sequences by recognizing mismatches in strand-exchange intermediates. In contrast to their equivalent roles during replication-error repair, mismatch recognition is more important for anti-recombination than subsequent mismatch processing. To obtain insight into this difference, ectopic substrates with 2% sequence divergence were used to examine mitotic recombination outcome (crossover or noncrossover; CO and NCO, respectively) and to infer molecular intermediates formed during double-strand break repair in Saccharomyces cerevisiae. Experiments were performed in an MMR-proficient strain, a strain with compromised mismatch-recognition activity (msh6Δ) and a strain that retained mismatch-recognition activity but was unable to process mismatches (mlh1Δ). While the loss of either mismatch binding or processing elevated the NCO frequency to a similar extent, CO events increased only when mismatch binding was compromised. The molecular features of NCOs, however, were altered in fundamentally different ways depending on whether mismatch binding or processing was eliminated. These data suggest a model in which mismatch recognition reverses strand-exchange intermediates prior to the initiation of end extension, while subsequent mismatch processing that is linked to end extension specifically destroys NCO intermediates that contain conflicting strand-discrimination signals for mismatch removal.
Authors
MLA Citation
Hum, Yee Fang, and Sue Jinks-Robertson. “Mismatch recognition and subsequent processing have distinct effects on mitotic recombination intermediates and outcomes in yeast.Nucleic Acids Res, vol. 47, no. 9, May 2019, pp. 4554–68. Pubmed, doi:10.1093/nar/gkz126.
URI
https://scholars.duke.edu/individual/pub1387997
PMID
30809658
Source
pubmed
Published In
Nucleic Acids Res
Volume
47
Published Date
Start Page
4554
End Page
4568
DOI
10.1093/nar/gkz126

Regulation of hetDNA Length during Mitotic Double-Strand Break Repair in Yeast.

Heteroduplex DNA (hetDNA) is a key molecular intermediate during the repair of mitotic double-strand breaks by homologous recombination, but its relationship to 5' end resection and/or 3' end extension is poorly understood. In the current study, we examined how perturbations in these processes affect the hetDNA profile associated with repair of a defined double-strand break (DSB) by the synthesis-dependent strand-annealing (SDSA) pathway. Loss of either the Exo1 or Sgs1 long-range resection pathway significantly shortened hetDNA, suggesting that these pathways normally collaborate during DSB repair. In addition, altering the processivity or proofreading activity of DNA polymerase δ shortened hetDNA length or reduced break-adjacent mismatch removal, respectively, demonstrating that this is the primary polymerase that extends both 3' ends. Data are most consistent with the extent of DNA synthesis from the invading end being the primary determinant of hetDNA length during SDSA.
Authors
Guo, X; Hum, YF; Lehner, K; Jinks-Robertson, S
MLA Citation
Guo, Xiaoge, et al. “Regulation of hetDNA Length during Mitotic Double-Strand Break Repair in Yeast.Mol Cell, vol. 67, no. 4, Aug. 2017, pp. 539-549.e4. Pubmed, doi:10.1016/j.molcel.2017.07.009.
URI
https://scholars.duke.edu/individual/pub1271598
PMID
28781235
Source
pubmed
Published In
Mol Cell
Volume
67
Published Date
Start Page
539
End Page
549.e4
DOI
10.1016/j.molcel.2017.07.009

Research Areas:

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