The BRCA1-PALB2-BRCA2 axis in the DNA damage response and cancer development
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.
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
Dynamique de l'information génétique : bases fondamentales et cancer (DIG-Cancer) (UMR3244)