Targeting the nucleotide salvage factor DNPH1 sensitizes <em>BRCA</em>-deficient cells to PARP inhibitors

doi:10.1126/science.abb4542

GSTDTAP > 气候变化

DOI	10.1126/science.abb4542
	*Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors*
	Kasper Fugger; Ilirjana Bajrami; Mariana Silva Dos Santos; Sarah Jane Young; Simone Kunzelmann; Geoff Kelly; Graeme Hewitt; Harshil Patel; Robert Goldstone; Thomas Carell; Simon J. Boulton; James MacRae; Ian A. Taylor; Stephen C. West
	2021-04-09
发表期刊	Science
出版年	2021
英文摘要	BRCA1 and BRCA2 are tumor-suppressor genes, and patients with mutations in these genes are predisposed to breast, ovarian, and other cancers. Because BRCA1 and BRCA2 mutations affect pathways involved in DNA break repair, these patients' tumors are usually vulnerable to treatments that further damage DNA repair, such as poly(ADP-ribose) polymerase (PARP) inhibitors, but they can acquire resistance to therapy. Using a genome-wide screening approach, Fugger et al. identified a protein called DNPH1 as a “nucleotide sanitizer” that prevents the incorporation of abnormal nucleotides into DNA (see the Perspective by Kriaucionis). The authors examined its mechanism of action and demonstrated how it can be targeted to expedite the killing of BRCA1 -mutant cancer cells in combination with PARP inhibitor treatment. Science , this issue p. [156][1]; see also p. [127][2] Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA -deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1 -deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA -deficient cancers to PARPi therapy. [1]: /lookup/doi/10.1126/science.abb4542 [2]: /lookup/doi/10.1126/science.abh3188
领域	气候变化 ; 资源环境
URL	查看原文
引用统计	被引频次：60[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/322089
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Kasper Fugger,Ilirjana Bajrami,Mariana Silva Dos Santos,et al. Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors[J]. Science,2021.
APA	Kasper Fugger.,Ilirjana Bajrami.,Mariana Silva Dos Santos.,Sarah Jane Young.,Simone Kunzelmann.,...&Stephen C. West.(2021).Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors.Science.
MLA	Kasper Fugger,et al."Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors".Science (2021).