Distinct ATRX functions cooperate with 9-1-1 and CST complexes to safeguard replication and telomere integrity
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Sandra Segura-Bayona Marija Maric Tohru Takaki Zornitsa Manova Tyler Stanage Aurora Idilli Shudong Li Graeme Hewitt Feras Machour Rhona Millar Marek Adamowicz Ronnie Ren Jie Low Phil Ruis Benura Azeroglu Todd Fallesen Harshil Patel Steven Howell Panagiotis Kotsantis Michael Howell Simon BoultonAbstract
Mutations in the ATRX chromatin remodeler confer a predisposition to a developmental genetic disorder and cancer, but how ATRX safeguards genome and telomere stability remains unresolved. Here, we uncover critical dependencies for the CTC1-STN1-TEN1 (CST) complex and RAD9A-HUS1-RAD1 (9-1-1) clamp in ATRX-deficient cells. ATRX-CST synthetic lethality manifests following accumulation of telomeric G-rich single-stranded DNA (ssDNA), which results in telomere loss and cell death. Conversely, we attribute ATRX-9-1-1 synthetic lethality to genome-wide ssDNA lesions, which compromise DNA replication. We further show that ATRX suppresses DNA damage during replication stress by counteracting the activity of the FAM111A protease. We demonstrate that roles of ATRX in telomere maintenance and replication are genetically separable, requiring its ATPase activity and PIP-box, respectively. We also show that such roles protecting genome stability are largely independent of the ATRX-DAXX interaction. Collectively, our data show that functions of ATRX in suppressing toxic ssDNA lesions are context-dependent and are key to global DNA replication and telomere integrity.
Journal details
Volume
33
Issue number
7
Pages
1037-1050
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10.1038/s41594-026-01827-2
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Europe PubMed Central
42380617
Pubmed
42380617
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The publication was previously a preprint.
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