Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

Martin R. Higgs; Koichi Sato; John J. Reynolds; Shabana Begum; Rachel Bayley; Amalia Goula; Audrey Vernet; Karissa L. Paquin; David G. Skalnik; Wataru Kobayashi; Minoru Takata; Niall G. Howlett; Hitoshi Kurumizaka; Hiroshi Kimura; Grant S. Stewart

doi:10.1016/j.molcel.2018.05.018

Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

Martin R. Higgs, Koichi Sato, John J. Reynolds, Shabana Begum, Rachel Bayley, Amalia Goula, Audrey Vernet, Karissa L. Paquin, David G. Skalnik, Wataru Kobayashi, Minoru Takata, Niall G. Howlett, Hitoshi Kurumizaka, Hiroshi Kimura, Grant S. Stewart

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

34 Citations (Scopus)

Abstract

Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks.

Original language	English
Pages (from-to)	25-41.e6
Journal	Molecular Cell
Volume	71
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2018.05.018
Publication status	Published - 2018 Jul 5

Keywords

BOD1L
FANCD2
histone methylation
lysine methyltransferase
replication fork replication
replication stress
SETD1A

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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Higgs, M. R., Sato, K., Reynolds, J. J., Begum, S., Bayley, R., Goula, A., Vernet, A., Paquin, K. L., Skalnik, D. G., Kobayashi, W., Takata, M., Howlett, N. G., Kurumizaka, H., Kimura, H., & Stewart, G. S. (2018). Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2. Molecular Cell, 71(1), 25-41.e6. https://doi.org/10.1016/j.molcel.2018.05.018

Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2. / Higgs, Martin R.; Sato, Koichi; Reynolds, John J.; Begum, Shabana; Bayley, Rachel; Goula, Amalia; Vernet, Audrey; Paquin, Karissa L.; Skalnik, David G.; Kobayashi, Wataru; Takata, Minoru; Howlett, Niall G.; Kurumizaka, Hitoshi; Kimura, Hiroshi; Stewart, Grant S.

In: Molecular Cell, Vol. 71, No. 1, 05.07.2018, p. 25-41.e6.

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

Higgs, MR, Sato, K, Reynolds, JJ, Begum, S, Bayley, R, Goula, A, Vernet, A, Paquin, KL, Skalnik, DG, Kobayashi, W, Takata, M, Howlett, NG, Kurumizaka, H, Kimura, H & Stewart, GS 2018, 'Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2', Molecular Cell, vol. 71, no. 1, pp. 25-41.e6. https://doi.org/10.1016/j.molcel.2018.05.018

Higgs, Martin R. ; Sato, Koichi ; Reynolds, John J. ; Begum, Shabana ; Bayley, Rachel ; Goula, Amalia ; Vernet, Audrey ; Paquin, Karissa L. ; Skalnik, David G. ; Kobayashi, Wataru ; Takata, Minoru ; Howlett, Niall G. ; Kurumizaka, Hitoshi ; Kimura, Hiroshi ; Stewart, Grant S. / Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2. In: Molecular Cell. 2018 ; Vol. 71, No. 1. pp. 25-41.e6.

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abstract = "Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks.",

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AU - Bayley, Rachel

AU - Goula, Amalia

AU - Vernet, Audrey

AU - Paquin, Karissa L.

AU - Skalnik, David G.

AU - Kobayashi, Wataru

AU - Takata, Minoru

AU - Howlett, Niall G.

AU - Kurumizaka, Hitoshi

AU - Kimura, Hiroshi

AU - Stewart, Grant S.

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AB - Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks.

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Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

Abstract

Keywords

ASJC Scopus subject areas

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