H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours

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H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours. / Dibitetto, Diego; Liptay, Martin; Vivalda, Francesca; Dogan, Hülya; Gogola, Ewa; González Fernández, Martín; Duarte, Alexandra; Schmid, Jonas A.; Decollogny, Morgane; Francica, Paola; Przetocka, Sara; Durant, Stephen T.; Forment, Josep V.; Klebic, Ismar; Siffert, Myriam; de Bruijn, Roebi; Kousholt, Arne N.; Marti, Nicole A.; Dettwiler, Martina; Sørensen, Claus S.; Tille, Jean Christophe; Undurraga, Manuela; Labidi-Galy, Intidhar; Lopes, Massimo; Sartori, Alessandro A.; Jonkers, Jos; Rottenberg, Sven.

I: Nature Communications, Bind 15, 4430, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Dibitetto, D, Liptay, M, Vivalda, F, Dogan, H, Gogola, E, González Fernández, M, Duarte, A, Schmid, JA, Decollogny, M, Francica, P, Przetocka, S, Durant, ST, Forment, JV, Klebic, I, Siffert, M, de Bruijn, R, Kousholt, AN, Marti, NA, Dettwiler, M, Sørensen, CS, Tille, JC, Undurraga, M, Labidi-Galy, I, Lopes, M, Sartori, AA, Jonkers, J & Rottenberg, S 2024, 'H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours', Nature Communications, bind 15, 4430. https://doi.org/10.1038/s41467-024-48715-1

APA

Dibitetto, D., Liptay, M., Vivalda, F., Dogan, H., Gogola, E., González Fernández, M., Duarte, A., Schmid, J. A., Decollogny, M., Francica, P., Przetocka, S., Durant, S. T., Forment, J. V., Klebic, I., Siffert, M., de Bruijn, R., Kousholt, A. N., Marti, N. A., Dettwiler, M., ... Rottenberg, S. (2024). H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours. Nature Communications, 15, [4430]. https://doi.org/10.1038/s41467-024-48715-1

Vancouver

Dibitetto D, Liptay M, Vivalda F, Dogan H, Gogola E, González Fernández M o.a. H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours. Nature Communications. 2024;15. 4430. https://doi.org/10.1038/s41467-024-48715-1

Author

Dibitetto, Diego ; Liptay, Martin ; Vivalda, Francesca ; Dogan, Hülya ; Gogola, Ewa ; González Fernández, Martín ; Duarte, Alexandra ; Schmid, Jonas A. ; Decollogny, Morgane ; Francica, Paola ; Przetocka, Sara ; Durant, Stephen T. ; Forment, Josep V. ; Klebic, Ismar ; Siffert, Myriam ; de Bruijn, Roebi ; Kousholt, Arne N. ; Marti, Nicole A. ; Dettwiler, Martina ; Sørensen, Claus S. ; Tille, Jean Christophe ; Undurraga, Manuela ; Labidi-Galy, Intidhar ; Lopes, Massimo ; Sartori, Alessandro A. ; Jonkers, Jos ; Rottenberg, Sven. / H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours. I: Nature Communications. 2024 ; Bind 15.

Bibtex

@article{ea3b9a540bd8480a8e4a579b3680d0bb,

title = "H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours",

abstract = "Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.",

author = "Diego Dibitetto and Martin Liptay and Francesca Vivalda and H{\"u}lya Dogan and Ewa Gogola and {Gonz{\'a}lez Fern{\'a}ndez}, Mart{\'i}n and Alexandra Duarte and Schmid, {Jonas A.} and Morgane Decollogny and Paola Francica and Sara Przetocka and Durant, {Stephen T.} and Forment, {Josep V.} and Ismar Klebic and Myriam Siffert and {de Bruijn}, Roebi and Kousholt, {Arne N.} and Marti, {Nicole A.} and Martina Dettwiler and S{\o}rensen, {Claus S.} and Tille, {Jean Christophe} and Manuela Undurraga and Intidhar Labidi-Galy and Massimo Lopes and Sartori, {Alessandro A.} and Jos Jonkers and Sven Rottenberg",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s41467-024-48715-1",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours

AU - Dibitetto, Diego

AU - Liptay, Martin

AU - Vivalda, Francesca

AU - Dogan, Hülya

AU - Gogola, Ewa

AU - González Fernández, Martín

AU - Duarte, Alexandra

AU - Schmid, Jonas A.

AU - Decollogny, Morgane

AU - Francica, Paola

AU - Przetocka, Sara

AU - Durant, Stephen T.

AU - Forment, Josep V.

AU - Klebic, Ismar

AU - Siffert, Myriam

AU - de Bruijn, Roebi

AU - Kousholt, Arne N.

AU - Marti, Nicole A.

AU - Dettwiler, Martina

AU - Sørensen, Claus S.

AU - Tille, Jean Christophe

AU - Undurraga, Manuela

AU - Labidi-Galy, Intidhar

AU - Lopes, Massimo

AU - Sartori, Alessandro A.

AU - Jonkers, Jos

AU - Rottenberg, Sven

PY - 2024

Y1 - 2024

N2 - Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

AB - Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

U2 - 10.1038/s41467-024-48715-1

DO - 10.1038/s41467-024-48715-1

M3 - Journal article

C2 - 38789420

AN - SCOPUS:85194218303

VL - 15

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4430

ER -

ID: 395024962