Radiation-induced double-strand breaks (DSBs) are fundamental threats to genomic integrity that result in genomic instability if not properly repaired, which can in turn lead to cancer and cell death. Although we know a great deal about the pathways of DSB repair, we know very little about how DSB repair occurs in its natural context in the cell, that is, chromatin. Chromatin by its very nature is an impediment for proteins accessing the DNA, yet the repair machinery is somehow able to navigate through the chromatin and successfully repair DNA damage. Chromatin also plays a key role in transducing the cell's response to DNA damage via the DNA damage cell cycle checkpoint. Until recently, there has been a large gap in our understanding as to how the DSB repair and the DNA damage checkpoint are influenced by the chromatin environment in mammalian cells. Integral to this process is the progression of the DNA repair machinery along a genome that is packaged into chromatin; how this occurs and the influence on the epigenome, has been a long-standing mystery. We have recently shown that chromatin is completely disassembled and reassembled during non-homologous end joining of double-strand DNA breaks in human cells. Excitingly, our recent preliminary data strongly supports an active role for dynamic chromatin assembly onto single stranded DNA (ssDNA) in the midst of homologous recombinational repair of DSBs as an intrinsic step required for DSB repair. Histones occupying ssDNA has never been reported previously in vivo, let alone their playing an important biological role. The proposed studies will uncover the nature of the histone-DNA complexes on ssDNA, and will reveal the elusive mechanism whereby chromatin assembly promotes DSB repair in human cells. By elucidating the mechanism whereby ssDNA-histone complexes contribute to DSB repair, we hope to fill significant gaps in our current knowledge of the chromosomal repair process.
Despite the fundamental importance of maintaining genomic stability, there are still huge gaps in our knowledge of the biological processes that maintain genomic stability and the repair of radiation damage. Understanding how packaging our genome into chromatin influences these process will provide key insights into their regulation. The proposed studies will fill these knowledge gaps by uncovering the nature and role of novel intermediates in the repair process that we have uncovered, and will leverage these discoveries to identify targeted therapies to maintain genomic stability in the face of radiation.
|Hu, Zheng; Xia, Bo; Postnikoff, Spike Dl et al. (2018) Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan. Elife 7:|
|Huang, Ting-Hsiang; Fowler, Faith; Chen, Chin-Chuan et al. (2018) The Histone Chaperones ASF1 and CAF-1 Promote MMS22L-TONSL-Mediated Rad51 Loading onto ssDNA during Homologous Recombination in Human Cells. Mol Cell 69:879-892.e5|
|Tyler, Jessica K; Johnson, Jay E (2018) The role of autophagy in the regulation of yeast life span. Ann N Y Acad Sci 1418:31-43|
|Hung, Putzer J; Chen, Bo-Ruei; George, Rosmy et al. (2017) Deficiency of XLF and PAXX prevents DNA double-strand break repair by non-homologous end joining in lymphocytes. Cell Cycle 16:286-295|
|Postnikoff, Spike D L; Johnson, Jay E; Tyler, Jessica K (2017) The integrated stress response in budding yeast lifespan extension. Microb Cell 4:368-375|
|Fowler, Faith; Tyler, Jessica K (2017) Anchoring Chromatin Loops to Cancer. Dev Cell 42:209-211|
|Aguilar, Rhiannon R; Tyler, Jessica K (2017) Thinking Outside the Cell: Replicating Replication In Vitro. Mol Cell 65:5-7|
|Diao, Li-Ting; Chen, Chin-Chuan; Dennehey, Briana et al. (2017) Delineation of the role of chromatin assembly and the Rtt101Mms1 E3 ubiquitin ligase in DNA damage checkpoint recovery in budding yeast. PLoS One 12:e0180556|
|Wang, Pingping; Byrum, Stephanie; Fowler, Faith C et al. (2017) Proteomic identification of histone post-translational modifications and proteins enriched at a DNA double-strand break. Nucleic Acids Res 45:10923-10940|
|Graves, Hillary K; Wang, Pingping; Lagarde, Matthew et al. (2016) Mutations that prevent or mimic persistent post-translational modifications of the histone H3 globular domain cause lethality and growth defects in Drosophila. Epigenetics Chromatin 9:9|
Showing the most recent 10 out of 45 publications