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Philipp Oberdoerffer, Ph.D.

Portait Photo of Philipp Oberdoerffer
Laboratory of Receptor Biology and Gene Expression
Head, Epigenetics of DNA Repair and Aging Section
Center for Cancer Research
National Cancer Institute
Building 41, Room B907
41 Library Drive, MSC 5055
Bethesda, MD 20892


In 2004, Dr. Oberdoerffer obtained his Ph.D. in Genetics and Immunology under the supervision of Dr. Klaus Rajewsky at the University of Cologne, Germany. He then joined Dr. David Sinclair's group at Harvard Medical School, first as a National Space Biomedical Research Institute (NSBRI) Investigator, and later as a Leukemia and Lymphoma Society Special Fellow. In 2009, he joined the Mouse Cancer Genetics Program at the Center for Cancer Research, NCI where he studies the molecular link between DNA damage, chromatin and aging. In 2013, Dr. Oberdoerffer joined the Laboratory for Receptor Biology and Gene Expression at NCI.


DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions that can result in cell cycle arrest, cell death or malignant transformation. In addition to the often detrimental effects of mutations and chromosomal rearrangements caused by aberrant DSB repair, DNA breaks pose a significant threat to the epigenomic integrity of eukaryotic cells. Perhaps most notably, DSBs promote an extensive, structural reorganization of break-proximal chromatin to facilitate and control repair factor access. Moreover, accumulating evidence suggests that DNA breakage is associated with epigenetic changes that reach beyond the sites of damage, resulting in transcriptional deregulation and, ultimately, nuclear dysfunction. Elucidating the crosstalk between DSB formation and chromatin organization is, thus, vital not only to provide mechanistic insight into the regulation of DSB repair, but also to improve our understanding of DNA damage-associated epigenomic changes that occur during organismal decline and malignant transformation. To achieve these goals, my research program (i) investigates the role of chromatin (modifiers) in repair factor recruitment, pathway choice and genome maintenance, and (ii) seeks to define the extent of DSB-induced chromatin reorganization and its functional consequences in vivo.

We found previously that DNA damage can cause the redistribution of the chromatin modifier Sirt1 from promoters and repetitive DNA to sites of DNA breaks. While this process appears to be critical for genome maintenance, it comes at the cost of SIRT1 target gene deregulation, which mirrors aspects of the transcriptional changes observed with age. This work led to the more general hypothesis that DNA damage-induced chromatin reorganization may underlie the alterations in gene expression and genomic stability that characterize malignant transformation, degenerative diseases and defective tissue maintenance. In support of the latter, recent work from our lab demonstrated a dual role for Sirt1 in hematopoietic stem and progenitor cell (HSPCs) homeostasis, involving both epigenetic silencing of a key HSPC developmental regulator, Hoxa9, and assurance of genomic stability in these adult stem cells.

Our more recent efforts aim to dissect the interplay between DNA damage and chromatin beyond the role of Sirt1, with a focus on regulators of DSB repair. DSB repair generally occurs through one of two pathways: non-homologous end joining (NHEJ), which is by nature error- prone, or homologous recombination (HR), which restores the original DNA sequence using undamaged template DNA. Appropriate repair pathway choice is essential to ensure accurate repair outcome and defects in both HR and NHEJ have been linked to immune deficiency, cancer predisposition and other diseases. We currently (i) investigate the hypothesis that (selective) histone variant incorporation may serve as a central aspect of DSB repair pathway choice, and (ii) aim to indentify possible roles of other (repressive) histone marks and modifiers in selective repair factor recruitment. Together, this work is expected to further our understanding of how chromatin reorganization can control the balance between 53BP1 and BRCA1-mediated DSB repair pathways, which has important consequences for DSB repair in general and BRCA1-dependent genome maintenance in particular.

This page was last updated on 12/9/2013.