PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response

• Published in: Oncogene Vol. 38; no. 10; pp. 1585 - 1596
• Main Authors: Simhadri, Srilatha, Vincelli, Gabriele, Huo, Yanying, Misenko, Sarah, Foo, Tzeh Keong, Ahlskog, Johanna, Sørensen, Claus S., Oakley, Gregory G., Ganesan, Shridar, Bunting, Samuel F., Xia, Bing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2019; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/31; 13/89; 631/67/68; 631/80/641/1655; 82/29; Animals; Apoptosis; Biotechnology; BRCA1 protein; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; BRCA2 protein; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Cell Biology; Cell Line, Tumor; Cells (Biology); Checkpoint Kinase 1 - metabolism; Checkpoint Kinase 2 - metabolism; CHK1 protein; Chromosomes; Cooperativity; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Epistasis; Fanconi Anemia Complementation Group N Protein - genetics; Fanconi Anemia Complementation Group N Protein - metabolism; G2 Phase Cell Cycle Checkpoints; Genetic aspects; Genomes; Genomics; HCT116 Cells; HEK293 Cells; Homologous recombination; Human Genetics; Humans; Internal Medicine; Ionizing radiation; Laboratory rats; Medicine; Medicine & Public Health; Mice; Oncology; Phosphorylation; Proteins; Radiation (Physics); Recombinational DNA Repair; Tumor suppressor genes; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0535-2

The G2/M checkpoint inhibits mitotic entry upon DNA damage, thereby preventing segregation of broken chromosomes and preserving genome stability. The tumor suppressor proteins BRCA1, PALB2 and BRCA2 constitute a BRCA1–PALB2–BRCA2 axis that is essential for homologous recombination (HR)-based DNA doublestrand break repair. Besides HR, BRCA1 has been implicated in both the initial activation and the maintenance of the G2/M checkpoint, while BRCA2 and PALB2 have been shown to be critical for its maintenance. Here we show that all three proteins can play a significant role in both checkpoint activation and checkpoint maintenance, depending on cell type and context, and that PALB2 links BRCA1 and BRCA2 in the checkpoint response. The BRCA1–PALB2 interaction can be important for checkpoint activation, whereas the PALB2–BRCA2 complex formation appears to be more critical for checkpoint maintenance. Interestingly, the function of PALB2 in checkpoint response appears to be independent of CHK1 and CHK2 phosphorylation. Following ionizing radiation, cells with disengaged BRCA1–PALB2 interaction show greatly increased chromosomal abnormalities due apparently to combined defects in HR and checkpoint control. These findings provide new insights into DNA damage checkpoint control and further underscore the critical importance of the proper cooperation of the BRCA and PALB2 proteins in genome maintenance.