PALB2/FANCN: recombining cancer and Fanconi anemia

Abstract

Partner and localizer of BRCA2 (PALB2) was originally identified as a BRCA2-interacting protein that is crucial for key BRCA2 genome caretaker functions. It subsequently became clear that PALB2 was another Fanconi anemia (FA) gene (FANCN), and that monoallelic PALB2 mutations are associated with increased risk of breast and pancreatic cancer. Mutations in PALB2 have been identified in breast cancer families worldwide, and recent studies have shown that PALB2 also interacts with BRCA1. Here, we summarize the molecular functions and clinical phenotypes of this key DNA repair pathway component and discuss how its discovery has advanced our knowledge of both FA and adult cancer predisposition.

Figure 1. The BRCA complex of HR repair and tumor suppression

(A) The PALB2 gene locus in chromosome 16p12.2. The image is generated using the NCBI Sequence Viewer and slightly modified. (B) Schematic of the PALB2 protein structure showing its domains responsible for binding with BRCA1, BRCA2 and MRG15. (C) A proposed model of BRCA complex assembly at sites of DNA double strand breaks. It is currently unclear which BRCA1 BRCT domain binding partners (BRIP1/FANCJ, CCDC98-RAP80 or CtIP) exist in the core BRCA1/PALB2/BRCA2 complex. Also, BRCA1 may be recruited to damage sites via two distinct mechanisms- one by interacting with the MRE11/RAD50/NBS1 (MRN) complex and the other via its binding to the CCDC98/RAP80 complex, and it remains to be seen which branch is responsible for PALB2/BRCA2/RAD51 recruitment.