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Friday, July 8th, 2022
Centre de recherche - Paris - Amphithéâtre Constant-Burg (12 rue Lhomond, Paris 5e) en visio-conférence avec l'amphithéâtre du bâtiment 111 (Orsay) et salle Clavel (Saint-Cloud)

The BRCA1-PALB2-BRCA2 axis in the DNA damage response and cancer development

Bing Xia

The major breast cancer susceptibility genes BRCA1 and BRCA2 encode very large and completely distinct proteins that play essential roles in the DNA damage response (DDR), especially in the repair of DNA double strand breaks (DSBs) by homologous recombination (HR), cell cycle checkpoint control, and stabilization of stalled replication forks. PALB2 was discovered as a major binding protein of BRCA2 required for the intranuclear localization, stability, and the DNA damage response functions of the latter. Later, PALB2 was found to also directly interacts with BRCA1 and links BRCA1 and BRCA2 in the HR pathway, G2/M checkpoint control, and tumor suppression. Consistent with its close physical and functional association with BRCA2 and BRCA1, germline pathogenic mutations in PALB2 have been found in breast, ovarian, pancreatic, prostate and gastric cancers and Fanconi anemia. To date, cumulative results from several large international studies have established the risk of female breast cancer by 80 years of age caused by germline pathogenic PALB2 mutations being ~40% overall and ~53% in families with a history of the disease, qualifying PALB2 as a high-risk breast cancer gene. Here, I will summarize the knowledge gained from both functional studies and mouse models and discuss the role of DNA damage, oxidative stress, and autophagy in the pathogenesis of PALB2-associated breast and other cancers. I will then present our recent work on the role of BRCA2 and PALB2 in the regulation of DNA replication kinetics after DNA damage and the importance of the BRCA1-PALB2 interaction for tumor suppression in different tissues.



Prof. Bing Xia

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA

Hosted by

Dr. Chunlong Chen
Group leader
Dynamique de l'information génétique : bases fondamentales et cancer (DIG-Cancer) (UMR3244)

Institut Curie

To sum up

The major goal of my research is to understand how hereditary breast cancers develop and how to prevent and better treat them. Our primary focus is the cellular and genetic mechanisms of cancer development associated with mutations in BRCA1/2 and PALB2 tumor suppressors. Specifically, we study the mechanisms of the BRCA1-PALB2-BRCA2 axis in the DNA damage response and the roles of DNA damage, oxidative stress, and autophagy in BRCA/PALB2-associated cancer development. I have made significant contributions to the DNA repair and cancer genetics fields, particularly through the discovery of the PALB2 tumor suppressor and the establishment of the BRCA1-PALB2-BRCA2 DNA damage response and tumor suppression pathway. Additionally, work from my laboratory has shed light on the roles of oxidative stress and autophagy in breast cancer. Ongoing and recently completed projects that I would like to highlight include: R01 CA262227-01, National Cancer Institute (NCI) Xia, Bing (PI) 07/01/21-06/30/26 Regulation of DNA replication kinetics by BRCA2 after DNA damage P01 CA250957-01A1, National Cancer Institute (NCI) Xia, Bing (PL) 05/01/21-04/30/26 (Project 2) Targeting DNA replication in BRCA-associated breast cancer R01 CA138804-11, National Cancer Institute (NCI) Xia, Bing (PI) 07/01/20-06/30/25 Role of PALB2 in the DNA Damage Response and Cancer Suppression R01 CA188096-01A1, National Cancer Institute (NCI)
Xia, Bing (PI)
Targeting Autophagy in Hereditary Breast Cancer