Richard Kolodner
University of California-San Diego, CA·Genetics
Cells copy and repair DNA constantly, and when those processes fail, mutations and gross chromosomal rearrangements, or GCRs, accumulate. GCRs are large-scale losses, breaks, and swaps of chromosome segments, and they are a hallmark and driver of many inherited and sporadic cancers.
- Fields
Genetics
Biochemistry
Pharmacology
- Topics
genome instability
gross chromosomal rearrangements
DNA mismatch repair
- Grants
- 4 known grants, through Aug 2027
What they work on
- Identify human genes whose loss sensitizes cells to potent FEN1 inhibitors through expanded CRISPR-dropout screens in cell lines and mice, defining synthetic lethal partners of this flap-trimming endonuclease.
- Mine cancer omics and gene essentiality datasets, with cell-based validation, to define the spectrum of cancers and molecular signatures amenable to FEN1 inhibitor treatment.
- Test whether FEN1 inhibition causes irreparable replication fork damage in BRCA1- and BRCA2-mutant cells, and compare mechanisms of acquired resistance to FEN1 versus PARP inhibitors.
- Quantify FEN1 essentiality across ten Ewing sarcoma cell lines using validated siRNAs and CRISPR/Cas9, and measure inhibitor cytotoxicity in 2D and 3D culture, including synergy with current chemotherapies.
- Determine whether the EWS-FLI1 fusion oncoprotein induces FEN1 dependency in Ewing sarcoma, and test the inhibitor SMD154 against orthotopic xenografts and patient-derived xenografts in mice.
- Use yeast genetics to find new mismatch repair proteins and Msh2- and Mlh1-interacting partners, and to determine how the Mlh1-Pms1 endonuclease is activated.
- Reconstitute mismatch repair from purified proteins to compare mispair excision by Exo1, by the Rad27 endonuclease, and by Mlh1-Pms1 alone, resolving interactions with surface plasmon resonance and single-molecule biochemistry.
- Dissect how Tor2, the cohesin and condensin complexes, and Exonuclease 1 suppress gross chromosomal rearrangements in Saccharomyces cerevisiae, using whole-genome sequencing and a PCR assay that tracks individual rearrangement events.
- Develop gross chromosomal rearrangement assays for human cells and apply them to defects in human genome instability suppressor genes first identified in yeast.
More about the research
Four projects span the distance between basic mechanism and therapy. Two use baker's yeast, Saccharomyces cerevisiae, to dissect how cells normally prevent mutations and rearrangements. Two translate a specific vulnerability discovered through that yeast genetics into drugs aimed at cancers whose DNA repair is already broken.
Why it matters
The translational projects could yield treatments aimed squarely at genome instability: FEN1 inhibitors for breast and ovarian cancers lacking BRCA1 or BRCA2 function, and for Ewing sarcoma, where advanced disease carries a five-year survival below 30 percent and no new targeted options have emerged. The yeast work could improve clinical tests of a tumor's mismatch repair status, which predicts response to immunotherapy and some chemotherapies, and clarify where genome instability in cancer originates.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Jason Yustein
Emory University, GA·Medicine & Clinical Research
Map single-cell protein and RNA signatures and cell-cell communication in MYC-amplified human and mouse osteosarcoma, using patient-derived xenografts and engineered mice, and disrupt candidate metastasis-linked signals genetically.
Juan Lucas Argueso
Colorado State University-Fort Collins, CO·Genetics
Measure rates of copy number variation (CNV), loss of heterozygosity (LOH), and whole-chromosome gain or loss in dividing and meiotic budding yeast cells, using custom, highly sensitive cell-based assays.
David Benner Lombard
University of Miami, FL·Medicine & Clinical Research
Determine how SIRT5, an enzyme that strips succinyl tags from proteins, controls histone succinylation and gene expression in Ewing sarcoma cells, using mass spectrometry with transcriptomic and epigenomic profiling.
The school
University of California-San Diego: 84 labs on PI Pages, $1.9B a year on research, 637 research doctorates a year.
Reach out
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