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

Srilatha Simhadri; Gabriele Vincelli; Yanying Huo; Sarah Misenko; Tzeh Keong Foo; Johanna Ahlskog; Claus S. Sørensen; Gregory G. Oakley; Shridar Ganesan; Samuel F. Bunting; Bing Xia

doi:10.1038/s41388-018-0535-2

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

Srilatha Simhadri, Gabriele Vincelli, Yanying Huo, Sarah Misenko, Tzeh Keong Foo, Johanna Ahlskog, Claus S. Sørensen, Gregory G. Oakley, Shridar Ganesan, Samuel F. Bunting, Bing Xia^*

^*Corresponding author for this work

16 Citations (Scopus)

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.

Original language	English
Journal	Oncogene
Volume	38
Pages (from-to)	1585–1596
Number of pages	12
ISSN	0950-9232
DOIs	https://doi.org/10.1038/s41388-018-0535-2
Publication status	Published - 7 Mar 2019

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@article{e55f804badc04338a9f2b1816ed6d3e0,

title = "PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response",

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.",

author = "Srilatha Simhadri and Gabriele Vincelli and Yanying Huo and Sarah Misenko and Foo, {Tzeh Keong} and Johanna Ahlskog and S{\o}rensen, {Claus S.} and Oakley, {Gregory G.} and Shridar Ganesan and Bunting, {Samuel F.} and Bing Xia",

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doi = "10.1038/s41388-018-0535-2",

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TY - JOUR

T1 - PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response

AU - Simhadri, Srilatha

AU - Vincelli, Gabriele

AU - Huo, Yanying

AU - Misenko, Sarah

AU - Foo, Tzeh Keong

AU - Ahlskog, Johanna

AU - Sørensen, Claus S.

AU - Oakley, Gregory G.

AU - Ganesan, Shridar

AU - Bunting, Samuel F.

AU - Xia, Bing

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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.

AB - 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.

U2 - 10.1038/s41388-018-0535-2

DO - 10.1038/s41388-018-0535-2

M3 - Journal article

C2 - 30337689

AN - SCOPUS:85055104510

SN - 0950-9232

VL - 38

SP - 1585

EP - 1596

JO - Oncogene

JF - Oncogene

ER -

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

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