The goal of this proposed work is to characterize the function of the histone demethylase, LSD1, in the DNA damage response (DDR). LSD1 has been shown to regulate many genes and act in a number of distinct biological and pathological pathways, particularly in cancer. Small molecule inhibitors of LSD1 have begun to be characterized in preclinical studies;indeed, these show promise as a novel modality for epigenetic therapy for a number of different types of cancer. However, the function of LSD1 in the DDR pathway and its role in genomic stability is just beginning to be uncovered. Preliminary results, using a combination of biochemistry, molecular biology and cell biology, reveal that LSD1 functions in the DDR pathway upstream of the 53BP1 tumor suppressor. These results demonstrate that LSD1 performs this function by regulation of ubiquitylation at sites of DNA damage. The hypothesis that LSD1 functions directly in this pathway and is a critical component of the DDR machinery will be tested by a number of biochemical and molecular strategies. The work proposed here will be conducted under the mentorship of Dr. Yang Shi, discoverer of LSD1 and a world leader in chromatin research. The candidate is an M.D., Ph.D. with training in clinical pathology and seeks further training in basic research. The long-term goal is to establish and direct an independent research laboratory studying the role of chromatin in genomic maintenance. It is anticipated that the project will yield important insight into the mechanisms of genomic stability and will prepare the candidate for a career as an independent investigator.

Public Health Relevance

The research proposed in this grant has significance for the way in which cells guard their genome, a pathway important for cancer development. The proposed studies will shed light on the molecular mechanisms in this pathway, and may lead to novel diagnostic and therapeutic avenues in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA158133-01
Application #
8091922
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2011-08-17
Project End
2012-06-01
Budget Start
2011-08-17
Budget End
2012-06-01
Support Year
1
Fiscal Year
2011
Total Cost
$179,280
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Soll, Jennifer M; Sobol, Robert W; Mosammaparast, Nima (2017) Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities. Trends Biochem Sci 42:206-218
Zhao, Yu; Majid, Mona C; Soll, Jennifer M et al. (2015) Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase. EMBO J 34:1687-703
Zhao, Yu; Brickner, Joshua R; Majid, Mona C et al. (2014) Crosstalk between ubiquitin and other post-translational modifications on chromatin during double-strand break repair. Trends Cell Biol 24:426-34
Tubbs, Anthony T; Dorsett, Yair; Chan, Elizabeth et al. (2014) KAP-1 promotes resection of broken DNA ends not protected by ?-H2AX and 53BP1 in G?-phase lymphocytes. Mol Cell Biol 34:2811-21
Mosammaparast, Nima; Kim, Haeyoung; Laurent, Benoit et al. (2013) The histone demethylase LSD1/KDM1A promotes the DNA damage response. J Cell Biol 203:457-70
Dango, Sebastian; Mosammaparast, Nima; Sowa, Mathew E et al. (2011) DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. Mol Cell 44:373-84