Philipp Oberdoerffer, Ph.D.
Laboratory of Receptor Biology and Gene Expression
Building 41, Room B907
Bethesda, MD 20892
In the Epigenetics of DNA Repair and Aging Section (EDRA), we use a combination of mouse models and cell-based approaches to address fundamental questions related to the complex crosstalk between chromatin, DNA repair and cellular dysfunction, We are particularly interested in DNA double-strand break (DSB) repair via homologous recombination (HR), which plays a central role in the cellular response to replication stress – a major source of endogenous DNA damage that is tightly linked to both cellular senescence and cancer susceptibility.
Our lab has made significant advances in understanding the epigenetic consequences of DNA damage in vivo. Using a mouse model that allows for temporally and spatially defined DSB induction, we recently uncovered an unexpected capacity of primary cells to maintain transcriptome integrity in response to acute DSB exposure. By combining ChIP-Seq, transcriptome profiling and chromatin interactome data, we now aim to dissect the epigenetic impact of chronic DSB induction with unprecedented, three-dimensional resolution.
In an orthogonal approach, we have identified novel, chromatin-related mediators of DNA repair by HR using a focused RNA interference (RNAi). In so doing we found that the repressive macro-histone variant macroH2A1.2 can regulate HR by modulating DSB-proximal chromatin to promote BRCA1-dependent genome maintenance. Our ongoing studies suggest that macroH2A1.2 is also a critical, protective component of the replication stress response, with direct implications for cellular senescence and tumor growth. Of note, macroH2A1.2 represents one of two alternative splice variants of the macroH2A1 (H2AFY) gene, which have seemingly opposing roles during DNA repair and cell growth and are differentially expressed in a variety of human tumors. Analyses of unique macroH2A1 splice variant interactomes and features are ongoing.
Liu J, Kruswick A, Dang H, Tran AD, Kwon SM, Wang XW, Oberdoerffer P. Ubiquitin-specific protease 21 stabilizes BRCA2 to control DNA repair and tumor growth. Nat Commun. 2017;8(1):137.
Kim J, Sturgill D, Tran AD, Sinclair DA, Oberdoerffer P. Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability. Nucleic Acids Res. 2016;44(7):e64.
Khurana S, Oberdoerffer P. Replication Stress: A Lifetime of Epigenetic Change. Genes (Basel). 2015;6(3):858-77.
Khurana S, Kruhlak MJ, Kim J, Tran AD, Liu J, Nyswaner K, Shi L, Jailwala P, Sung MH, Hakim O, Oberdoerffer P. A macrohistone variant links dynamic chromatin compaction to BRCA1-dependent genome maintenance. Cell Rep. 2014;8(4):1049-62.
Singh SK, Williams CA, Klarmann K, Burkett SS, Keller JR, Oberdoerffer P. Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance. J Exp Med. 2013;210(5):987-1001.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on February 4th, 2019