DOI: 10.1101/2023.05.22.541781

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

D.Dibitetto M. Liptay F. Vivalda E. Gogola H. Dogan M. G. Fernandez A. Duarte J. A. Schmid S. T. Durant J. V. Forment I. Klebic M. Siffert R. de Brujin A. N. Kousholt N. A. Marti

D.Dibitetto M. Liptay F. Vivalda ...+17 S. Rottenberg

摘要

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs)1,2. In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as {gamma}H2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA13,4,5,6. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours7,8, we identify a novel function for {gamma}H2AX in orchestrating drug-induced replication fork degradation. Mechanistically, {gamma}H2AX-dependent replication fork degradation is elicited by the inhibition of 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 inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection of stalled forks. In summary, our results demonstrate a novel 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.

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