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The Highly Parallel Homology Directed Repair Assay and the Analysis of BRCA1 Variants

Islam, Muhtadi
http://orcid.org/0000-0002-9813-9427
http://rave.ohiolink.edu/etdc/view?acc_num=osu1462561237

Abstract Details

, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
DNA damage and repair are processes that have been linked to cancer, both in carcinogenesis and in the treatment of cancer. We explore two different DNA repair factors, BRCA1 and HDAC10, in two distinct studies. BRCA1 is a highly penetrant gene in both breast and ovarian cancer and with several functions. We analyze BRCA1 in a novel assay that scores the homologous recombination repair function of several thousand BRCA1 variants in parallel. Our goal is to create a structure function map of BRCA1 at the amino acid resolution to not only prove the novel highly parallel functional assay, but also to provide clinically relevant data of BRCA1 variants with respect to homologous recombination repair. HDAC10 is a histone deacetylase with only one known function, stimulating homologous recombination repair of double strand breaks. Utilizing genome databases, we found that HDAC10 is deleted in up to 10% of ovarian tumors. We also found that low HDAC10 expression correlated with platinum therapy sensitivity. We demonstrated general HDAC inhibition enhanced cisplatin therapy in primary ovarian carcinomas. Additionally, HDAC10 specific inhibition sensitized a BRCA1 deficient ovarian cancer cell line to both DNA damage and cisplatin therapy. We suggest that HDAC10 is an important agent in the mechanisms of general HDAC inhibition as well as a potential new target for BRCA1 deficient ovarian tumors.
Jeffrey Parvin (Advisor)
Michael Freitas (Committee Member)
Kun Huang (Committee Member)
Amanda Toland (Committee Member)
130 p.
Biomedical Research

Recommended Citations

Citations

  • Islam, M. (2016). The Highly Parallel Homology Directed Repair Assay and the Analysis of BRCA1 Variants [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1462561237

    APA Style (7th edition)

  • Islam, Muhtadi. The Highly Parallel Homology Directed Repair Assay and the Analysis of BRCA1 Variants. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1462561237.

    MLA Style (8th edition)

  • Islam, Muhtadi. "The Highly Parallel Homology Directed Repair Assay and the Analysis of BRCA1 Variants." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1462561237

    Chicago Manual of Style (17th edition)

osu1462561237
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© 2016, some rights reserved.Creative Commons License The Highly Parallel Homology Directed Repair Assay and the Analysis of BRCA1 Variants by Muhtadi Islam is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.