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SILAC-iPOND analysis of WT vs ATRX KO eHAP cells ± HU

ABSTRACT: Mutations in the ATRX chromatin remodeller predispose 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 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Sandra Segura-Bayona

LAB HEAD: Simon Boulton

PROVIDER: PXD068487 | Pride | 2026-05-19

REPOSITORIES: Pride

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			Action	DRS
	20210624_BI2217_Mix1_1.raw	Raw
	20210624_BI2217_Mix1_2.raw	Raw
	20210624_BI2217_Mix1_3.raw	Raw
	20210624_BI2217_Mix1_4.raw	Raw
	20210624_BI2217_Mix2_1.raw	Raw

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