Our group is looking to recruit a postdoctoral fellow/associate to join the laboratory of Daniel Higginson in the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center. We study DNA double strand break repair with a special focus on the role of alternative end-joining (Alt-EJ) in cancer-specific contexts, such as tumors deficient in homologous recombination. The projects involve a mixture of basic science projects in molecular biology and translational projects involving detection of Alt-EJ usage in human specimens and cancer genomes.
We are a supportive and collegial group and would like to recruit researchers interested in cutting edge techniques and clinically impactful science. Outside-the-box ideas inspired by a candidate’s previous experience are also encouraged. Four of the primary projects are listed here and also on the lab website (https://www.mskcc.org/research-areas/labs/daniel-higginson/overview).
1. HPV oncoproteins and alternative end-joining
HPV-associated squamous cell carcinomas are highly radiosensitive when compared to their HPV negative comparators, a phenomenon that is consistent for aerodigestive and anogenital cancers. Our group characterized the DNA double strand break defect in HPV-associated cancers using three methodologies and found corroborating evidence by identifying a microhomology-based indel genomic signature in HPV-associated cancer genomes reflective of increased Alt-EJ usage (PMID 31591214). We continue to study basic mechanisms of how HPV oncoproteins affect DNA repair capacity and pathway choice. Involved techniques would include CRISPR-Cas9, patient derived xenografts, confocal microscopy, and single cell sequencing.
2. Technology development: improving measurement of primary and alterative DSB repair pathways
With support from the NCI and the Innovative Molecular Analysis Technology (IMAT) program (1R33CA236670-01A1), we develop innovative new tools to measure both primary and secondary DNA DSB repair pathways by comprehensively profiling insertions and deletions of all sizes. With support from the Emerson Collective Cancer Research Fund, we apply these tools to human specimens to measure repair capacity in human tumors.
3. End-resection, end-protection and ALT-EJ regulation
Alt-EJ is at least partly mediated through a factor known as polymerase theta, which mediates annealing and repair of short segments of microhomology typically located within 15 bp from the breaksite. End-resection is highly regulated with multiple mechanisms to limit resection to S and G2 portions of the cell cycle when complementary sister chromatid DNA is available for homologous recombination. However, Alt-EJ requires only short-range resection in contrast to HR. In addition, the 53BP1-Shieldin axis protects ends from resection, but apparently requires exposed single strand DNA to operate. Using optogenetic control of Cas9-induced breaks, we study how short-range resection, end protection, and cell cycle phase regulate Alt-EJ utilization.
4. Matching radiosensitizing DNA damage response inhibitors (DDRi) to repair deficiencies in cancer
An array of small molecular inhibitors targeting components of the DNA damage response have entered phase I clinical trials, including inhibitors of the ATM, ATR, and DNApkcs kinases. Though clearly radiosensitizing, it is not clear how these agents might improve the therapeutic window of responses to radiation between tumor and normal cells. Using repair profiling of DNA repair capacity, we seek to find novel categories of tumors with improved therapeutic windows when matched to an optimized DDRi.
Please send CVs and cover letters and we will contact you in 1-2 weeks.
Tagged as: Life Sciences
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