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

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
Number of pages	24
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

A549 Cells
DNA/biosynthesis
DNA Replication/physiology
Epigenesis, Genetic/physiology
Fanconi Anemia Complementation Group D2 Protein/genetics
HeLa Cells
Histone-Lysine N-Methyltransferase/genetics
Histones/genetics
Humans
Methylation
Molecular Chaperones/genetics
Nucleosomes/genetics
Rad51 Recombinase/genetics

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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

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title = "Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2",

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.",

keywords = "A549 Cells, DNA/biosynthesis, DNA Replication/physiology, Epigenesis, Genetic/physiology, Fanconi Anemia Complementation Group D2 Protein/genetics, HeLa Cells, Histone-Lysine N-Methyltransferase/genetics, Histones/genetics, Humans, Methylation, Molecular Chaperones/genetics, Nucleosomes/genetics, Rad51 Recombinase/genetics",

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

year = "2018",

month = jul,

day = "5",

doi = "10.1016/j.molcel.2018.05.018",

language = "English",

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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

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T1 - Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

AU - Higgs, Martin R

AU - Sato, Koichi

AU - Reynolds, John J

AU - Begum, Shabana

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

PY - 2018/7/5

Y1 - 2018/7/5

N2 - 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.

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.

KW - A549 Cells

KW - DNA/biosynthesis

KW - DNA Replication/physiology

KW - Epigenesis, Genetic/physiology

KW - Fanconi Anemia Complementation Group D2 Protein/genetics

KW - HeLa Cells

KW - Histone-Lysine N-Methyltransferase/genetics

KW - Histones/genetics

KW - Humans

KW - Methylation

KW - Molecular Chaperones/genetics

KW - Nucleosomes/genetics

KW - Rad51 Recombinase/genetics

UR - https://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30392-7

U2 - 10.1016/j.molcel.2018.05.018

DO - 10.1016/j.molcel.2018.05.018

M3 - Article

C2 - 29937342

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

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Keywords

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