Molecular Biosciences
Bing Xia

Bing Xia
Associate Professor

Robert Wood Johnson Medical School
Department of Radiation Oncology
The Cancer Institute of NJ
195 Little Albany Street, Room 4562
New Brunswick, NJ 08901
(732) 235-7410
FAX - 7493

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.

Selected Publications

Huo Y, Cai H, Teplova I, Bowman-Colin C, Chen G, Price S, Barnard N, Ganesan S, Karantza V, White E and Xia B. (2013) Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer. Cancer Discovery (Epub ahead of print) PMID: 23650262

Bowman-Colin C, Xia B, Bunting S, Klijn C, Drost R, Bouwman P, Fineman L, Chen X, Culhane AC, Cai H, Rodig SJ, Bronson RT, Jonkers J, Nussenzweig A, Kanellopoulou C# and Livingston DM# (2013) Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer. Proc Natl Acad Sci USA 110:8632-7. PMID: 23657012

Anantha RW, Alcivar AL, Ma J, Cai H, Simhadri S, Ule J, König J and Xia B. (2013) Requirement of heterogeneous nuclear ribonucleoprotein C for BRCA gene expression and homologous recombination. PloS One e61368. PMID: 23585894

Kim JH, Xu EY, Sacks DB, Lee J, Shu L, Xia B and Kong AN. (2012) Identification and Functional Studies of a New Nrf2 partner IQGAP1: A critical role in the stability and transactivation of Nrf2. Antioxid Redox Signal (Epub ahead of print) PMID: 22793650

Ma J, Cai H, Wu T, Sobhian B, Huo Y, Mehta M, Cheung KL, Ganesan S, Kong T, Zhang DD and Xia B (2012) PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Mol Cell Biol 32:1506-17.

Siaud N, Barbera MA, Egashira A, Lam I, Christ N, Schlacher K, Xia B, and Jasin M (2011) Plasticity of BRCA2 function in homologous recombination: Genetic interactions of the PALB2 and DNA binding domains. PloS Genet 7:e1002409.

Tu Z, Aird KM, Bitler BG, Nicodemus JP, Beeharry N, Xia B, Yen TJ, Zhang R (2011) Oncogenic Ras Regulates BRIP1 Expression to Induce Dissociation of BRCA1 from Chromatin, Inhibit DNA Repair, and Promote Senescence. Dev Cell 21:1077-91.

Jirawatnotai S, Hu Y, Michowski W, Elias JE, Becks L, Bienvenu F, Zagozdzon A, Goswami T, Wang YE, Clark AB, Kunkel TA, van Harn T, Xia B, Correll M, Quackenbush J, Livingston DM, Gygi SP and Sicinski P (2011) A function for cyclin D1 in DNA repair uncovered by interactome analyses in human cancers. Nature 474:230-4.

Buisson, R., Dion-Côté, A.M., Launay, H, Coulombe Y., Cai, H., Stasiak, A.Z., Stasiak, A., Xia, B. and Masson J.Y. (2010) Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol 17:1247-54.

Tischkowitz, M. and Xia, B. (2010) PALB2/FANCN-recombining cancer and Fanconi anemia. Cancer Res 70:7353-9.

Shen X, Do H, Li Y, Chung WH, Tomasz M, de Winter JP, Xia B, Elledge SJ, Wang W, Li L. (2009) Recruitment of fanconi anemia and breast cancer proteins to DNA damage sites is differentially governed by replication. Mol Cell. 35(5):716-23.

Zhang, F*, Ma, J*, Wu, J*, Ye, L, Cai, H, Xia, B# and Yu, X.# (2009) PALB2 links BRCA1 and BRCA2 in the DNA damage response. Curr Biol 19: 524–529. (# co-corresponding authors)

Sobhian, B., Shao, G., Lilly, D.R., Culhane, A., Moreau, L., Xia, B., Livingston, D.M. and Greenberg, R.A. (2007) Rap80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316:1198-1202.

Tischkowitz, M.*, Xia, B.*, Sabbaghian, N., Reis-Filho, J., Hamel, N., Li, G., van Beers, E., Li, L., Khalil, T., Quenneville, L., Omeroglu, A., Poll, A., Lepage, P., Wong, N., Nederlof, P., Ashworth, A., Rahman, N., Tonin, P.N., Narod, S.A., Livingston, D.M. and Foulkes, W.D. (2007) Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA 104:6788-6793.

Erkko, H.*, Xia, B.*, Nikkilä, J., Schleutker, J., Syrjäkoski, K., Mannermaa, A., Kallioniemi, A., Pylkäs, K., Karppinen, S., Rapakko, K., Miron, A., Sheng, Q., Li, G., Mattila, H., Bell, D.W., Haber, D.A., Grip, M., Jukkola-Vuorinen, A., Mustonen, A., Kere, J., Altonen, L.A., Kosma, V., Kataja, V., Soini, Y., Drapkin, R.I., Livingston, D.M. and Winqvist, R. (2007) A recurrent mutation in PALB2 in Finnish cancer families. Nature 446: 316-319.

Xia, B.*, Dorsman, J.C.*, Ameziane, N., de Vries, Y., Rooimans, M.A., Sheng, Q., Pals, G., Errami, A., Gluckman, E., Llera, J., Wang, W., Livingston, D.M., Joenje, H. and de Winter, J.P. (2007) Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nature Genet 39:165-167.

Xia, B., Sheng, Q., Nakanishi, K., Ohashi, A., Wu, J., Christ, N., Liu, X., Jasin, M., Couch, F.J., and Livingston, D.M. (2006) Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 22: 719-729.

* These authors contribute equally to the work.