Elucidating the Role of MMS22L on Uterine Epithelium
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Date
2017-05
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The Ohio State University
Abstract
Targeted gene therapy and DNA repair inhibition have been compelling areas of interest for personalized medicine and cancer treatment. For example, recent work has identified the MMS22L-TONSL DNA repair complex as a novel marker on post-replicative chromatin necessary for cell viability, RAD51 loading, DNA repair, and overall genomic stability in vitro. Depletion of MMS22L-TONSL in cancer cells results in decreased proliferation and a reduction of viability in vitro. Furthermore, elevated levels of TONSL have been noted in several cancers implicating MMS22L as a novel target for cancer therapy. To validate these findings in more complex systems before advancing to clinical trials, we utilized a transgenic loss-of-function system in 2 month-old and 6 month-old-mice to elucidate the consequence of MMS22L deletion in uterine development and proliferation.
Given our findings of embryonic lethality for globally deleted Mms22l, the fluctuating expression of MMS22L through the estrus cycle in endometrial epithelial cells, and the dynamic nature of the mouse endometrium; tissue-specific deletion in mouse endometrial epithelial cells using the tissue-specific Cre- recombinase system (Sprr2f-Cre) was conducted. We found that loss of Mms22l in the uterine epithelium results in increased DNA damage and reduced reproductive function. All things considered, we demonstrate the impact of Mms22l deletion in mouse endometrial epithelial cells and on adult uterine physiology and reproduction in order to validate the MMS22L-TONSL complex as a potential target for endometrial cancer and build the foundation for in vivo studies of Mms22l.
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Keywords
Uterine Development, Endometrial Cancer, MMS22L, Mouse Model