<br>H2AX 促进 BRCA 缺陷肿瘤的复制叉降解和化疗敏感性,Nature Communications

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H2AX 促进 BRCA 缺陷肿瘤的复制叉降解和化疗敏感性
Nature Communications ( IF 14.7 ) Pub Date : 2024-05-24 , DOI: 10.1038/s41467-024-48715-1
Diego Dibitetto _{1,

2,

3} , Martin Liptay _{1,

2} , Francesca Vivalda ₄ , Hülya Dogan _{1,

2} , Ewa Gogola _{5,

6} , Martín González Fernández _{1,

2} , Alexandra Duarte _{5,

6} , Jonas A Schmid ₄ , Morgane Decollogny _{1,

2} , Paola Francica _{1,

2} , Sara Przetocka ₄ , Stephen T Durant ₇ , Josep V Forment ₇ , Ismar Klebic ₁ , Myriam Siffert ₁ , Roebi de Bruijn _{5,

6} , Arne N Kousholt _{6,

8} , Nicole A Marti _{1,

2} , Martina Dettwiler ₁ , Claus S Sørensen ₈ , Jean-Christophe Tille ₉ , Manuela Undurraga ₁₀ , Intidhar Labidi-Galy _{11,

12} , Massimo Lopes ₄ , Alessandro A Sartori ₄ , Jos Jonkers _{5,

6} , Sven Rottenberg _{1,

2,

5}

Affiliation

Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.
Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3012, Bern, Switzerland.
Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milan, Italy.
Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.
Oncode Institute, Amsterdam, The Netherlands.
DDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK.
Biotech Research and Innovation Centre, University of Copenhagen, 2200 N, Copenhagen, Denmark.
Division of Clinical Pathology, Department of Diagnostics, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
Division of Gynecology, Department of Pediatrics and Gynecology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
Faculty of Medicine, Department of Medicine and Center of Translational Research in Onco-Hematology, University of Geneva, Swiss Cancer Center Leman, Geneva, Switzerland.
Department of Oncology, Hôpitaux Universitaires de Genève, 4, Rue Gabrielle Perret-Gentil, Geneva, 1205, Switzerland.

组蛋白 H2AX 在 DNA 双链断裂 (DSB) 周围区域的 DNA 损伤信号传导中发挥着关键作用。为了响应 DNA 损伤，H2AX 在丝氨酸残基 139 上磷酸化（称为 γH2AX），导致 DNA 修复效应器 53BP1 和 BRCA1 的募集。在这里，通过研究 BRCA1/2 缺陷型乳腺肿瘤对聚（ADP-核糖）聚合酶（PARP）抑制剂的耐药性，我们确定了 γH2AX 在协调药物诱导的复制叉降解中的功能。从机制上讲，γH2AX 驱动的复制叉降解是通过抑制 CtIP 介导的复制叉保护引起的。因此，H2AX 丢失恢复了复制叉的稳定性，并增加了 BRCA1/2 缺陷肿瘤细胞的化疗耐药性，但没有恢复同源定向的 DNA 修复，正如缺乏 DNA 损伤诱导的 RAD51 病灶所强调的那样。此外，在试图发现获得性遗传脆弱性的过程中，我们发现 ATM 而不是 ATR 抑制通过干扰 CtIP 介导的分叉保护来克服 H2AX 缺陷肿瘤中的 PARP 抑制剂 (PARPi) 耐药性。总之，我们的结果证明了 H2AX 在 BRCA 缺陷肿瘤的复制叉生物学中的作用，并建立了 H2AX 的功能与其在 DNA 损伤信号传导和 DSB 修复中的经典作用分开。

"点击查看英文标题和摘要"

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

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.

更新日期：2024-05-26

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