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

Oncogene volume 38, pages 1585–1596 (2019)Cite this article

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Abstract

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.

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Acknowledgements

We thank Drs. J. Jonkers (Netherlands Cancer Institute) and D. Boothman (UT Southwestern Medical Center) for provision of the KB2 mouse mammary tumor cells and isogenic HCT116 cells, respectively. This work was supported by the National Institutes of Health (R01CA138804 and R01CA188096 to BX, R01CA190858 to SFB and R01CA169182 to SG). GV was supported by a postdoctoral fellowship and SM by a predoctoral fellowship from the New Jersey Commission for Cancer Research (NJCCR).

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    Authors and Affiliations

    1. Rutgers Cancer Institute of New Jersey, New Brunswick, USA

      Srilatha Simhadri, Gabriele Vincelli, Yanying Huo, Tzeh Keong Foo, Shridar Ganesan & Bing Xia

    2. Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA

      Srilatha Simhadri, Gabriele Vincelli, Yanying Huo, Tzeh Keong Foo & Bing Xia

    3. Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA

      Srilatha Simhadri & Shridar Ganesan

    4. Department of Molecular Biology and Biochemistry, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

      Sarah Misenko & Samuel F. Bunting

    5. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

      Johanna Ahlskog & Claus S. Sørensen

    6. Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE, 68583, USA

      Gregory G. Oakley

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    Correspondence to Bing Xia.

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    These authors contributed equally: Srilatha Simhadri, Gabriele Vincelli

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    Simhadri, S., Vincelli, G., Huo, Y. et al. PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response. Oncogene 38, 1585–1596 (2019). https://doi.org/10.1038/s41388-018-0535-2

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