Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability

Vincent Gaggioli; Calvin S.Y. Lo; Nazaret Reverón-Gómez; Zuzana Jasencakova; Heura Domenech; Hong Nguyen; Simone Sidoli; Andrey Tvardovskiy; Sidrit Uruci; Johan A. Slotman; Yi Chai; João G.S.C.Souto Gonçalves; Eleni Maria Manolika; Ole N. Jensen; David Wheeler; Sriram Sridharan; Sanjiban Chakrabarty; Jeroen Demmers; Roland Kanaar; Anja Groth; Nitika Taneja

doi:10.1038/s41556-023-01167-z

Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability

Vincent Gaggioli, Calvin S.Y. Lo, Nazaret Reverón-Gómez, Zuzana Jasencakova, Heura Domenech, Hong Nguyen, Simone Sidoli, Andrey Tvardovskiy, Sidrit Uruci, Johan A. Slotman, Yi Chai, João G.S.C.Souto Gonçalves, Eleni Maria Manolika, Ole N. Jensen, David Wheeler, Sriram Sridharan, Sanjiban Chakrabarty, Jeroen Demmers, Roland Kanaar, Anja GrothNitika Taneja^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

12 Citations (Scopus)

18 Downloads (Pure)

Abstract

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.

Original language	English
Journal	Nature Cell Biology
Volume	25
Issue number	7
Pages (from-to)	1017-1032
Number of pages	38
ISSN	1465-7392
DOIs	https://doi.org/10.1038/s41556-023-01167-z
Publication status	Published - 2023

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Publisher Copyright:
© 2023, The Author(s).

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Gaggioli, V., Lo, C. S. Y., Reverón-Gómez, N., Jasencakova, Z., Domenech, H., Nguyen, H., Sidoli, S., Tvardovskiy, A., Uruci, S., Slotman, J. A., Chai, Y., Gonçalves, J. G. S. C. S., Manolika, E. M., Jensen, O. N., Wheeler, D., Sridharan, S., Chakrabarty, S., Demmers, J., Kanaar, R., ... Taneja, N. (2023). Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability. Nature Cell Biology, 25(7), 1017-1032. https://doi.org/10.1038/s41556-023-01167-z

Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability. / Gaggioli, Vincent; Lo, Calvin S.Y.; Reverón-Gómez, Nazaret ; Jasencakova, Zuzana; Domenech, Heura; Nguyen, Hong; Sidoli, Simone; Tvardovskiy, Andrey; Uruci, Sidrit; Slotman, Johan A.; Chai, Yi; Gonçalves, João G.S.C.Souto; Manolika, Eleni Maria; Jensen, Ole N.; Wheeler, David; Sridharan, Sriram; Chakrabarty, Sanjiban; Demmers, Jeroen; Kanaar, Roland; Groth, Anja; Taneja, Nitika.

In: Nature Cell Biology, Vol. 25, No. 7, 2023, p. 1017-1032.

Research output: Contribution to journal › Journal article › Research › peer-review

Gaggioli, V, Lo, CSY, Reverón-Gómez, N , Jasencakova, Z, Domenech, H, Nguyen, H, Sidoli, S, Tvardovskiy, A, Uruci, S, Slotman, JA, Chai, Y, Gonçalves, JGSCS, Manolika, EM, Jensen, ON, Wheeler, D, Sridharan, S, Chakrabarty, S, Demmers, J, Kanaar, R, Groth, A & Taneja, N 2023, 'Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability', Nature Cell Biology, vol. 25, no. 7, pp. 1017-1032. https://doi.org/10.1038/s41556-023-01167-z

Gaggioli, Vincent ; Lo, Calvin S.Y. ; Reverón-Gómez, Nazaret ; Jasencakova, Zuzana ; Domenech, Heura ; Nguyen, Hong ; Sidoli, Simone ; Tvardovskiy, Andrey ; Uruci, Sidrit ; Slotman, Johan A. ; Chai, Yi ; Gonçalves, João G.S.C.Souto ; Manolika, Eleni Maria ; Jensen, Ole N. ; Wheeler, David ; Sridharan, Sriram ; Chakrabarty, Sanjiban ; Demmers, Jeroen ; Kanaar, Roland ; Groth, Anja ; Taneja, Nitika. / Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability. In: Nature Cell Biology. 2023 ; Vol. 25, No. 7. pp. 1017-1032.

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abstract = "Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.",

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AU - Domenech, Heura

AU - Nguyen, Hong

AU - Sidoli, Simone

AU - Tvardovskiy, Andrey

AU - Uruci, Sidrit

AU - Slotman, Johan A.

AU - Chai, Yi

AU - Gonçalves, João G.S.C.Souto

AU - Manolika, Eleni Maria

AU - Jensen, Ole N.

AU - Wheeler, David

AU - Sridharan, Sriram

AU - Chakrabarty, Sanjiban

AU - Demmers, Jeroen

AU - Kanaar, Roland

AU - Groth, Anja

AU - Taneja, Nitika

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N2 - Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.

AB - Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.

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