OncologyGenomic Instability and Cancer Laboratory
The recognition of many types of DNA lesions activates the cellular DNA damage response (DDR). The DDR orchestrates the appropriate cellular programs to maintain genome integrity after genotoxic stress. Indices of an activated DDR are evident in many pre-cancerous and cancerous lesions and it has been proposed to act as an inducible barrier to malignancy. This proposition is supported by both animal models and human genetic instability disorders that are caused by mutations in proteins that control the DDR. Understanding the signal transduction networks governed by the DDR, and the consequences of their impairment, will facilitate our understanding of tumor development and enhance cancer treatment methods.
Studies in our lab will focus on the role of the DDR in tumor suppression. Rare human diseases, including Ataxia-telangiectasia and Nijmegen Breakage Syndrome, lead to developmental disorders and tumor predisposition due to mutations in genes involved in the DDR. Using patient samples and murine models of the human diseases, we will analyze the molecular signaling that controls various components of the DDR and determine their role in tumor suppression.
1.The role of the Mre11 complex in tumor suppression.
Genetic studies in mice suggest that the G2/M checkpoint, which prevents cells with DNA damage from entering mitosis, is important for maintaining genome stability and suppressing cancer. We will further analyze the role of the Mre11 complex (Mre11, Rad50, Nbs1) in this checkpoint response, identify the cellular requirements to initiate and maintain the checkpoint, and determine its role in preventing malignancy.
2. The regulation of apoptosis by the Chk2 kinase.
The checkpoint kinase Chk2 plays a key role in triggering apoptosis in response to ionizing radiation and mice lacking Chk2 are resistant to radiation toxicity. We have observed that loss of Chk2 in mice with hypomorphic Mre11 complex mutations leads to a broad spectrum of tumors. To understand the role of Chk2 in tumor suppression we are analyzing its regulation by other members of the DDR and taking numerous approaches to identify relevant targets of its kinase activity.
Figure legend: A. Nbs1, a component of the Mre11 complex, localizes to the nucleus (top panel) and accumulates in foci at sites of damage following ionizing radiation (IR) treatment (bottom panel). B. Radiation induced chromosomal instability in mouse (top) or human (bottom) cells with mutations in the Mre11 complex. Chromatid breaks are indicated by red arrows. C. Tumors from mice with mutations in the Mre11 complex and Chk2. H&E stained sections of a high grade angiosarcoma (left) and a high grade osteogenic sarcoma (right) at 400X. Images courtesy of Sam Singer.
3. The influence of the damage response on chromatin composition.
The modulation of chromatin composition and the remodeling of DNA ends by the Mre11 complex and other DDR proteins is important for DNA repair as well as initiating the appropriate cellular responses. We will elucidate the signaling pathways that connect recognition of DNA lesions with essential changes in chromatin composition.
Group news & mentions
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