Robert Wood Johnson Medical School
Department of Radiation Oncology
The Cancer Institute of NJ, Room 4562
195 Little Albany Street
New Brunswick, NJ 08901
DNA repair, cell cycle checkpoints, oxidative stress, breast cancer, Fanconi anemia
The DNA damage response and oxidative stress response are critical cellular mechanisms that prevent the accumulation of mutations which leads to cancer, ageing and other diseases. BRCA1 and BRCA2 are important tumor suppressor proteins playing key roles in homologous recombination (HR), DNA double strand break repair (DSBR), cell cycle checkpoints, transcriptional regulation and, in case of BRCA1, oxidative stress protection. Monoallelic germline mutations in either gene predispose female carriers to breast and ovarian cancer, and such mutations in BRCA2 also increase the risk of pancreatic, male breast and prostate cancers. In addition, biallelic germline mutations in BRCA2 cause severe Fanconi anemia (FA), a rare cancer susceptibility syndrome affecting children.
In 2006, we reported the discovery of PALB2 as a major BRCA2 binding partner critical for its DNA repair and tumor suppression functions. Subsequently, we and others found a number of PALB2 mutations in familial breast cancer and FA patients, establishing PALB2 as a breast cancer tumor suppressor and a Fanconi anemia (FA) protein in its own right. To date, mutations in PALB2, albeit rare, have been found in cancer families in much of the world. Intriguingly, more recent work from our laboratory and others’ have further demonstrated that PALB2 also directly interacts with BRCA1 and links BRCA1 and BRCA2 in the HR-DSBR pathway. Finally, we also found that PALB2 participates in oxidative stress regulation by direct binding to KEAP1, a key sensor of oxidative stress and a powerful regulator of the master anti-oxidant transcriptional factor NRF2.
Currently, our laboratory is pursuing the following research themes: 1) biochemical purification of the BRCA1/PALB2/BRCA2 protein complexes aiming to identify new players and further mapping of the protein-protein interactions in this BRCA tumor suppression network; 2) structure-function analyses and mechanistic studies of BRCA1, BRCA2, PALB2, KEAP1 and NRF2 in DNA repair, cell cycle regulation and oxidative stress response; 3) Palb2 and Brca1/2 conditional knockout and Palb2 knockin mouse models; and 4) Functional characterization of clinically relevant BRCA1, BRCA2 and PALB2 mutations. Through these studies, we aim to discover the link(s) between the molecular actions of these proteins in above cellular processes and their abilities to suppress tumorigenesis, and hopefully contribute to the clinical management and treatment of the above-mentioned diseases.