BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation

Yunpeng Feng, Arsenios Vlassis, Céline Roques, Marie Eve Lalonde, Cristina González-Aguilera, Jean Philippe Lambert, Sung Bau Lee, Xiaobei Zhao, Constance Alabert, Jens V. Johansen, Eric Paquet, Xiang Jiao Yang, Anne Claude Gingras, Jacques Côté, Anja Groth

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

During DNA replication, thousands of replication origins are activated across the genome. Chromatin architecture contributes to origin specification and usage, yet it remains unclear which chromatin features impact on DNA replication. Here, we perform a RNAi screen for chromatin regulators implicated in replication control by measuring RPA accumulation upon replication stress. We identify six factors required for normal rates of DNA replication and characterize a function of the bromodomain and PHD finger-containing protein 3 (BRPF3) in replication initiation. BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14, and genomewide analysis shows high enrichment of BRPF3, HBO1 and H3K14ac at ORC1-binding sites and replication origins found in the vicinity of TSSs. Consistent with this, BRPF3 is necessary for H3K14ac at selected origins and efficient origin activation. CDC45 recruitment, but not MCM2-7 loading, is impaired in BRPF3-depleted cells, identifying a BRPF3-dependent function of HBO1 in origin activation that is complementary to its role in licencing. We thus propose that BRPF3-HBO1 acetylation of histone H3K14 around TSS facilitates efficient activation of nearby replication origins. Synopsis A distinct origin activation role of HBO1 acetyltransferase provides new insight into how demarcation of chromatin surrounding transcription start sites affects the regulation of nearby replication origins. siRNA screen identifies chromatin regulators important for DNA replication, including the scaffold protein BRPF3. BRPF3 regulates origin firing by directing the acetyltransferase HBO1 to target histone H3K14 in chromatin surrounding replication origins. HBO1-BRPF3 complex function in origin activation is separate from and complementary to HBO1-JADE1 function in origin licensing. Reduced origin activation upon BRPF3 depletion protects cells against replication stress-induced DNA damage. An RNAi screen for chromatin regulators of replication control reveals an origin activation role of HBO1 acetyltransferase role that is separate from its function in origin licensing.

Original languageEnglish
Pages (from-to)176-192
Number of pages17
JournalEMBO Journal
Volume35
Issue number2
Early online date30 Nov 2015
DOIs
Publication statusPublished - 18 Jan 2016

Fingerprint

Acetylation
Replication Origin
Histones
Fingers
Chemical activation
Chromatin
Proteins
DNA Replication
Acetyltransferases
Licensure
DNA
RNA Interference
Transcription Initiation Site
Scaffolds
Small Interfering RNA
DNA Damage
Genes

Keywords

  • BRPF
  • DNA replication
  • H3K14ac
  • HBO1
  • origin activation

Cite this

Feng, Y., Vlassis, A., Roques, C., Lalonde, M. E., González-Aguilera, C., Lambert, J. P., ... Groth, A. (2016). BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation. EMBO Journal, 35(2), 176-192. https://doi.org/10.15252/embj.201591293
Feng, Yunpeng ; Vlassis, Arsenios ; Roques, Céline ; Lalonde, Marie Eve ; González-Aguilera, Cristina ; Lambert, Jean Philippe ; Lee, Sung Bau ; Zhao, Xiaobei ; Alabert, Constance ; Johansen, Jens V. ; Paquet, Eric ; Yang, Xiang Jiao ; Gingras, Anne Claude ; Côté, Jacques ; Groth, Anja. / BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation. In: EMBO Journal. 2016 ; Vol. 35, No. 2. pp. 176-192.
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abstract = "During DNA replication, thousands of replication origins are activated across the genome. Chromatin architecture contributes to origin specification and usage, yet it remains unclear which chromatin features impact on DNA replication. Here, we perform a RNAi screen for chromatin regulators implicated in replication control by measuring RPA accumulation upon replication stress. We identify six factors required for normal rates of DNA replication and characterize a function of the bromodomain and PHD finger-containing protein 3 (BRPF3) in replication initiation. BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14, and genomewide analysis shows high enrichment of BRPF3, HBO1 and H3K14ac at ORC1-binding sites and replication origins found in the vicinity of TSSs. Consistent with this, BRPF3 is necessary for H3K14ac at selected origins and efficient origin activation. CDC45 recruitment, but not MCM2-7 loading, is impaired in BRPF3-depleted cells, identifying a BRPF3-dependent function of HBO1 in origin activation that is complementary to its role in licencing. We thus propose that BRPF3-HBO1 acetylation of histone H3K14 around TSS facilitates efficient activation of nearby replication origins. Synopsis A distinct origin activation role of HBO1 acetyltransferase provides new insight into how demarcation of chromatin surrounding transcription start sites affects the regulation of nearby replication origins. siRNA screen identifies chromatin regulators important for DNA replication, including the scaffold protein BRPF3. BRPF3 regulates origin firing by directing the acetyltransferase HBO1 to target histone H3K14 in chromatin surrounding replication origins. HBO1-BRPF3 complex function in origin activation is separate from and complementary to HBO1-JADE1 function in origin licensing. Reduced origin activation upon BRPF3 depletion protects cells against replication stress-induced DNA damage. An RNAi screen for chromatin regulators of replication control reveals an origin activation role of HBO1 acetyltransferase role that is separate from its function in origin licensing.",
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Feng, Y, Vlassis, A, Roques, C, Lalonde, ME, González-Aguilera, C, Lambert, JP, Lee, SB, Zhao, X, Alabert, C, Johansen, JV, Paquet, E, Yang, XJ, Gingras, AC, Côté, J & Groth, A 2016, 'BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation', EMBO Journal, vol. 35, no. 2, pp. 176-192. https://doi.org/10.15252/embj.201591293

BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation. / Feng, Yunpeng; Vlassis, Arsenios; Roques, Céline; Lalonde, Marie Eve; González-Aguilera, Cristina; Lambert, Jean Philippe; Lee, Sung Bau; Zhao, Xiaobei; Alabert, Constance; Johansen, Jens V.; Paquet, Eric; Yang, Xiang Jiao; Gingras, Anne Claude; Côté, Jacques; Groth, Anja.

In: EMBO Journal, Vol. 35, No. 2, 18.01.2016, p. 176-192.

Research output: Contribution to journalArticle

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AU - González-Aguilera, Cristina

AU - Lambert, Jean Philippe

AU - Lee, Sung Bau

AU - Zhao, Xiaobei

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N2 - During DNA replication, thousands of replication origins are activated across the genome. Chromatin architecture contributes to origin specification and usage, yet it remains unclear which chromatin features impact on DNA replication. Here, we perform a RNAi screen for chromatin regulators implicated in replication control by measuring RPA accumulation upon replication stress. We identify six factors required for normal rates of DNA replication and characterize a function of the bromodomain and PHD finger-containing protein 3 (BRPF3) in replication initiation. BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14, and genomewide analysis shows high enrichment of BRPF3, HBO1 and H3K14ac at ORC1-binding sites and replication origins found in the vicinity of TSSs. Consistent with this, BRPF3 is necessary for H3K14ac at selected origins and efficient origin activation. CDC45 recruitment, but not MCM2-7 loading, is impaired in BRPF3-depleted cells, identifying a BRPF3-dependent function of HBO1 in origin activation that is complementary to its role in licencing. We thus propose that BRPF3-HBO1 acetylation of histone H3K14 around TSS facilitates efficient activation of nearby replication origins. Synopsis A distinct origin activation role of HBO1 acetyltransferase provides new insight into how demarcation of chromatin surrounding transcription start sites affects the regulation of nearby replication origins. siRNA screen identifies chromatin regulators important for DNA replication, including the scaffold protein BRPF3. BRPF3 regulates origin firing by directing the acetyltransferase HBO1 to target histone H3K14 in chromatin surrounding replication origins. HBO1-BRPF3 complex function in origin activation is separate from and complementary to HBO1-JADE1 function in origin licensing. Reduced origin activation upon BRPF3 depletion protects cells against replication stress-induced DNA damage. An RNAi screen for chromatin regulators of replication control reveals an origin activation role of HBO1 acetyltransferase role that is separate from its function in origin licensing.

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Feng Y, Vlassis A, Roques C, Lalonde ME, González-Aguilera C, Lambert JP et al. BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation. EMBO Journal. 2016 Jan 18;35(2):176-192. https://doi.org/10.15252/embj.201591293