Reciprocal regulation between 53BP1 and the anaphase-promoting complex/cyclosome is required for genomic stability during mitotic stress

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Reciprocal regulation between 53BP1 and the anaphase-promoting complex/cyclosome is required for genomic stability during mitotic stress. / Kucharski, Thomas J; Minshall, Paul; Moustafa-Kamal, Mohamed; Turnell, Andrew; Teodoro, Jose.

In: Cell Reports, Vol. 18, No. 8, 21.02.2017, p. 1982-1995.

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Kucharski, Thomas J ; Minshall, Paul ; Moustafa-Kamal, Mohamed ; Turnell, Andrew ; Teodoro, Jose. / Reciprocal regulation between 53BP1 and the anaphase-promoting complex/cyclosome is required for genomic stability during mitotic stress. In: Cell Reports. 2017 ; Vol. 18, No. 8. pp. 1982-1995.

Bibtex

@article{1068b7357eda450fa6a9956d19426fde,
title = "Reciprocal regulation between 53BP1 and the anaphase-promoting complex/cyclosome is required for genomic stability during mitotic stress",
abstract = "The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor. Although 53BP1 function is not absolutely required for normal cell cycle progression, knockdown was highly toxic in combination with mitotic spindle poisons. Moreover, chemical inhibition of the APC/C was able to rescue the lethality of 53BP1 loss. Our findings reveal a reciprocal regulation between 53BP1 and APC/C that is required for response to mitotic stress and may contribute to the tumor-suppressor functions of 53BP1.",
keywords = "Mitosis, apc/c, 53BP1, genome stability",
author = "Kucharski, {Thomas J} and Paul Minshall and Mohamed Moustafa-Kamal and Andrew Turnell and Jose Teodoro",
year = "2017",
month = feb,
day = "21",
doi = "10.1016/j.celrep.2017.01.080",
language = "English",
volume = "18",
pages = "1982--1995",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "8",

}

RIS

TY - JOUR

T1 - Reciprocal regulation between 53BP1 and the anaphase-promoting complex/cyclosome is required for genomic stability during mitotic stress

AU - Kucharski, Thomas J

AU - Minshall, Paul

AU - Moustafa-Kamal, Mohamed

AU - Turnell, Andrew

AU - Teodoro, Jose

PY - 2017/2/21

Y1 - 2017/2/21

N2 - The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor. Although 53BP1 function is not absolutely required for normal cell cycle progression, knockdown was highly toxic in combination with mitotic spindle poisons. Moreover, chemical inhibition of the APC/C was able to rescue the lethality of 53BP1 loss. Our findings reveal a reciprocal regulation between 53BP1 and APC/C that is required for response to mitotic stress and may contribute to the tumor-suppressor functions of 53BP1.

AB - The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor. Although 53BP1 function is not absolutely required for normal cell cycle progression, knockdown was highly toxic in combination with mitotic spindle poisons. Moreover, chemical inhibition of the APC/C was able to rescue the lethality of 53BP1 loss. Our findings reveal a reciprocal regulation between 53BP1 and APC/C that is required for response to mitotic stress and may contribute to the tumor-suppressor functions of 53BP1.

KW - Mitosis

KW - apc/c

KW - 53BP1

KW - genome stability

U2 - 10.1016/j.celrep.2017.01.080

DO - 10.1016/j.celrep.2017.01.080

M3 - Article

VL - 18

SP - 1982

EP - 1995

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 8

ER -