The Tumor Suppressor PALB2: Inside Out. Issue 3 (March 2019) - Ducy, Mandy
Abstract : Partner and Localizer of BRCA2 (PALB2) has emerged as an important and versatile player in genome integrity maintenance. Biallelic mutations in PALB2 cause Fanconi anemia (FA) subtype FA-N, whereas monoallelic mutations predispose to breast, and pancreatic familial cancers. Herein, we review recent developments in our understanding of the mechanisms of regulation of the tumor suppressor PALB2 and its functional domains. Regulation of PALB2 functions in DNA damage response and repair occurs on multiple levels, including homodimerization, phosphorylation, and ubiquitylation. With a molecular emphasis, we present PALB2 -associated cancer mutations and their detailed analysis by functional assays. Highlights: The discovery of PALB2. The modes of regulation of PALB2 to restrain its activity to S/G2 phase of the cell cycle. Biochemical properties of PALB2 and also how it is regulated by dimerization, its ChAM domain, and by degradation during the G1 phase of the cell cycle. The regulation of PALB2 by phosphorylation by the ATR kinase and how it is recruited to chromatin by RNF168. Genetic defects in homologous recombination genes leading to cancer, with a focus on missense mutations and functional assays to measure PALB2 activity. The use of PARP inhibitors to treat not only BRCA1/2 -deficient cancers, but also other genetic defects, such as in PALB2, supports the exploitation of the PALB2-RAD52 synthetic lethal interaction as an anticancer approach.