Together, this work redefines ATRX as a dual-function guardian of genome stability, with implications for ATR-X syndrome and ATRX-mutant cancers.

🙏 Deeply grateful to all co-authors @boultonlab.bsky.social and @crick.ac.uk STPs for their outstanding support!

We uncover that ATRX restrains the recruitment of FAM111A to replication forks, thereby preventing DNA damage.

Distinct ATRX domains mediate these protective roles: ATPase activity suppresses telomeric ssDNA formation, while the PIP-box motif mitigates replication stress across the genome.

We identify that ATRX engages in distinct context-dependent genetic interactions: ATRX:CST synthetic lethality manifests following G-rich ssDNA accumulation & telomere loss, while ATRX:9-1-1 interaction emerges following replication fork collapse.

These findings highlight the role of endogenous replication stress in shaping cancer biology & therapy response.

Huge thanks to colleagues @crick.ac.uk @boultonlab.bsky.social and collaborators @thijnbrummel.bsky.social @thecesarelab.bsky.social for their brilliant support in this project!

When SLFN11 is lost, cells escape this safeguard, enabling immortalization and therapy resistance.

This helps explains why:
- SLFN11 is frequently inactivated in treatment-naïve cancers
- ALT-positive tumours tend to resist chemotherapy and have poor prognosis

Congratulations Puck and co-authors, this is such a beautiful paper!! 🌟