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.
In: Nature Communications, Vol. 15, 4430, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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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
N1 - Publisher Copyright: © The Author(s) 2024.
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