Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2

Martin Higgs; Koichi Sato; John Reynolds; Shabana Begum; Rachel Bayley; Amalia Goula; Audrey Vernet; Karissa Paquin; David Skalnik; Waturu Kobayashi; Minoru Takata; Niall Howlett; Hitoshi Kurumizaka; Hiroshi Kimura; Grant Stewart

doi:10.1016/j.molcel.2018.05.018

Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2

Martin Higgs, Koichi Sato, John Reynolds, Shabana Begum, Rachel Bayley, Amalia Goula, Audrey Vernet, Karissa Paquin, David Skalnik, Waturu Kobayashi, Minoru Takata, Niall Howlett, Hitoshi Kurumizaka, Hiroshi Kimura, Grant Stewart

Cancer and Genomic Sciences

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Abstract

Components of the Fanconi anaemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, thus 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 sensitises 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 via its ability to catalyse 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
Number of pages	23
Journal	Molecular Cell
Volume	71
Issue number	1
Early online date	21 Jun 2018
DOIs	https://doi.org/10.1016/j.molcel.2018.05.018
Publication status	Published - 5 Jul 2018

Keywords

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

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37 Citations
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On your marks, get SET(D1A): the race to protect stalled replication forks
Begum, S., Goula, A., Bayley, R. & Higgs, M., 2018, In: Molecular and Cellular Oncology. 5, 6, e1511209.
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216 Downloads (Pure)

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A novel epigenetic link between histone methylation and replication fork protection during replication stress
Higgs, M. (Invited speaker)
5 Jan 2018
Activity: Academic and Industrial events › Conference, workshop or symposium

Cite this

Higgs, M., Sato, K., Reynolds, J., Begum, S., Bayley, R., Goula, A., Vernet, A., Paquin, K., Skalnik, D., Kobayashi, W., Takata, M., Howlett, N., Kurumizaka, H., Kimura, H., & Stewart, G. (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

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abstract = "Components of the Fanconi anaemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, thus 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 sensitises 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 via its ability to catalyse 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.",

keywords = "replication stress, histone methylation, replication fork replication, FANCD2, SETD1A, BOD1L, lysine methyltransferase",

author = "Martin Higgs and Koichi Sato and John Reynolds and Shabana Begum and Rachel Bayley and Amalia Goula and Audrey Vernet and Karissa Paquin and David Skalnik and Waturu Kobayashi and Minoru Takata and Niall Howlett and Hitoshi Kurumizaka and Hiroshi Kimura and Grant Stewart",

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Higgs, M, Sato, K, Reynolds, J, Begum, S, Bayley, R , Goula, A, Vernet, A, Paquin, K, Skalnik, D, Kobayashi, W, Takata, M, Howlett, N, Kurumizaka, H, Kimura, H & Stewart, G 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

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T1 - Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2

AU - Higgs, Martin

AU - Sato, Koichi

AU - Reynolds, John

AU - Begum, Shabana

AU - Bayley, Rachel

AU - Goula, Amalia

AU - Vernet, Audrey

AU - Paquin, Karissa

AU - Skalnik, David

AU - Kobayashi, Waturu

AU - Takata, Minoru

AU - Howlett, Niall

AU - Kurumizaka, Hitoshi

AU - Kimura, Hiroshi

AU - Stewart, Grant

PY - 2018/7/5

Y1 - 2018/7/5

N2 - Components of the Fanconi anaemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, thus 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 sensitises 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 via its ability to catalyse 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.

AB - Components of the Fanconi anaemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, thus 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 sensitises 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 via its ability to catalyse 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.

KW - replication stress

KW - histone methylation

KW - replication fork replication

KW - FANCD2

KW - SETD1A

KW - BOD1L

KW - lysine methyltransferase

U2 - 10.1016/j.molcel.2018.05.018

DO - 10.1016/j.molcel.2018.05.018

M3 - Article

SN - 1097-2765

VL - 71

SP - 25-41.e6

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2

Abstract

Keywords

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On your marks, get SET(D1A): the race to protect stalled replication forks

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A novel epigenetic link between histone methylation and replication fork protection during replication stress

Cite this