The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining

Hubert Fleury; Myles K. MacEachern; Clara M. Stiefel; Roopesh Anand; Colin Sempeck; Benjamin Nebenfuehr; Kelper Maurer-Alcalá; Kerri Ball; Bruce Proctor; Ondrej Belan; Erin Taylor; Raquel Ortega; Benjamin Dodd; Laila Weatherly; Djelika Dansoko; Justin W. Leung; Simon J. Boulton; Nausica Arnoult

doi:10.1016/j.molcel.2023.03.017

The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining

Hubert Fleury, Myles K. MacEachern, Clara M. Stiefel, Roopesh Anand, Colin Sempeck, Benjamin Nebenfuehr, Kelper Maurer-Alcalá, Kerri Ball, Bruce Proctor, Ondrej Belan, Erin Taylor, Raquel Ortega, Benjamin Dodd, Laila Weatherly, Djelika Dansoko, Justin W. Leung, Simon J. Boulton, Nausica Arnoult

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous recombination (HR)-deficient tumors. Although targeting MMEJ has emerged as a powerful strategy to eliminate HR-deficient (HRD) cancers, this is limited by an incomplete understanding of the mechanism and factors required for MMEJ repair. Here, we identify the APE2 nuclease as an MMEJ effector. We show that loss of APE2 inhibits MMEJ at deprotected telomeres and at intra-chromosomal DSBs and is epistatic with Pol Theta for MMEJ activity. Mechanistically, we demonstrate that APE2 possesses intrinsic flap-cleaving activity, that its MMEJ function in cells depends on its nuclease activity, and further identify an uncharacterized domain required for its recruitment to DSBs. We conclude that this previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.

Original language	English (US)
Pages (from-to)	1429-1445.e8
Journal	Molecular Cell
Volume	83
Issue number	9
DOIs	https://doi.org/10.1016/j.molcel.2023.03.017
State	Published - May 4 2023

Keywords

APE2
APEX2
DNA repair
HR-deficient
Homologous Recombination
MMEJ
PARP
cancer
synthetic lethality

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2023.03.017

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Fleury, H., MacEachern, M. K., Stiefel, C. M., Anand, R., Sempeck, C., Nebenfuehr, B., Maurer-Alcalá, K., Ball, K., Proctor, B., Belan, O., Taylor, E., Ortega, R., Dodd, B., Weatherly, L., Dansoko, D., Leung, J. W., Boulton, S. J., & Arnoult, N. (2023). The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining. Molecular Cell, 83(9), 1429-1445.e8. https://doi.org/10.1016/j.molcel.2023.03.017

Fleury, H, MacEachern, MK, Stiefel, CM, Anand, R, Sempeck, C, Nebenfuehr, B, Maurer-Alcalá, K, Ball, K, Proctor, B, Belan, O, Taylor, E, Ortega, R, Dodd, B, Weatherly, L, Dansoko, D, Leung, JW, Boulton, SJ & Arnoult, N 2023, 'The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining', Molecular Cell, vol. 83, no. 9, pp. 1429-1445.e8. https://doi.org/10.1016/j.molcel.2023.03.017

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abstract = "Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous recombination (HR)-deficient tumors. Although targeting MMEJ has emerged as a powerful strategy to eliminate HR-deficient (HRD) cancers, this is limited by an incomplete understanding of the mechanism and factors required for MMEJ repair. Here, we identify the APE2 nuclease as an MMEJ effector. We show that loss of APE2 inhibits MMEJ at deprotected telomeres and at intra-chromosomal DSBs and is epistatic with Pol Theta for MMEJ activity. Mechanistically, we demonstrate that APE2 possesses intrinsic flap-cleaving activity, that its MMEJ function in cells depends on its nuclease activity, and further identify an uncharacterized domain required for its recruitment to DSBs. We conclude that this previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.",

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AU - Fleury, Hubert

AU - MacEachern, Myles K.

AU - Stiefel, Clara M.

AU - Anand, Roopesh

AU - Sempeck, Colin

AU - Nebenfuehr, Benjamin

AU - Maurer-Alcalá, Kelper

AU - Ball, Kerri

AU - Proctor, Bruce

AU - Belan, Ondrej

AU - Taylor, Erin

AU - Ortega, Raquel

AU - Dodd, Benjamin

AU - Weatherly, Laila

AU - Dansoko, Djelika

AU - Leung, Justin W.

AU - Boulton, Simon J.

AU - Arnoult, Nausica

PY - 2023/5/4

Y1 - 2023/5/4

N2 - Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous recombination (HR)-deficient tumors. Although targeting MMEJ has emerged as a powerful strategy to eliminate HR-deficient (HRD) cancers, this is limited by an incomplete understanding of the mechanism and factors required for MMEJ repair. Here, we identify the APE2 nuclease as an MMEJ effector. We show that loss of APE2 inhibits MMEJ at deprotected telomeres and at intra-chromosomal DSBs and is epistatic with Pol Theta for MMEJ activity. Mechanistically, we demonstrate that APE2 possesses intrinsic flap-cleaving activity, that its MMEJ function in cells depends on its nuclease activity, and further identify an uncharacterized domain required for its recruitment to DSBs. We conclude that this previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.

AB - Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous recombination (HR)-deficient tumors. Although targeting MMEJ has emerged as a powerful strategy to eliminate HR-deficient (HRD) cancers, this is limited by an incomplete understanding of the mechanism and factors required for MMEJ repair. Here, we identify the APE2 nuclease as an MMEJ effector. We show that loss of APE2 inhibits MMEJ at deprotected telomeres and at intra-chromosomal DSBs and is epistatic with Pol Theta for MMEJ activity. Mechanistically, we demonstrate that APE2 possesses intrinsic flap-cleaving activity, that its MMEJ function in cells depends on its nuclease activity, and further identify an uncharacterized domain required for its recruitment to DSBs. We conclude that this previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.

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KW - APEX2

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KW - Homologous Recombination

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KW - PARP

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KW - synthetic lethality

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ER -

The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining

Abstract

Keywords

ASJC Scopus subject areas

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