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SART3 promotes homologous recombination repair by stimulating DNA–RNA hybrids removal and DNA end resection

ABSTRACT: DNA–RNA hybrids triggered by double-strand breaks (DSBs) are crucial intermediates during DSB repair, and their timely resolution requires numbers of RNA helicases, including DEAD box 1 (DDX1). However, how these helicases are recruited to DSB-induced hybrids in time remains largely unclear. Here, we revealed that squamous cell carcinoma antigen recognized by T cells 3 (SART3) promotes DDX1 binding to DNA–RNA hybrids at DSBs for optimal homologous recombination (HR) repair. SART3 itself can associate with DNA–RNA hybrids and PAR chains, and is recruited to DSBs in both PARylation- and hybrid-dependent fashion. SART3 also associates with DDX1 and is necessary for DDX1 enrichment at DSBs. The defective SART3-DDX1 association observed in cells expressing the cancer-associated variant SART3-R836W not only abrogates the accumulation of DDX1 at DSBs, but also impairs hybrid removal and HR efficiency, leading to hypersensitivity of tumor cells to drug treatments. Interestingly, beyond impairing hybrid removal through DDX1, SART3 loss also inhibits DNA end resection, causing a more profound DSB repair defect and chemosensitivity. The stimulatory role of SART3 in end resection is mediated by its function to enhance USP15-BARD1 association and BRCA1-BARD1 retention. Together, our study reveals a previously unknown role of SART3 in DSB repair, rendering SART3 a promising target for cancer therapy.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: 慧傅

LAB HEAD: Caixia Guo

PROVIDER: PXD053595 | Pride | 2025-01-30

REPOSITORIES: pride

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			Action	DRS
	1-Vector.raw	Raw
	2-WT.raw	Raw
	3-XR.raw	Raw
	SFB-SART3-LC-MSMS-NC.xlsx	Xlsx
	checksum.txt	Txt

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