Evidence map›Paper›PMID 39497152›Full record

ArticleExperimental hematology & oncology2024

Nuclear porcupine mediates XRCC6/Ku70 S-palmitoylation in the DNA damage response.

Yang Chen, Mingming Xiao, Yaqi Mo, Jinlu Ma, Yamei Han, Qing Li, Qinghua Zeng, Rebecca J Boohaker, Joshua Fried, Yonghe Li and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Experimental hematology & oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Yang Chen *Department of Biochemistry and Molecular Biology, The Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
Mingming Xiao *Department of Biochemistry and Molecular Biology, The Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
Yaqi Mo *Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China.
Jinlu Ma *Department of Radiation Oncology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China.
Yamei HanDepartment of Biochemistry and Molecular Biology, The Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
Qing LiChongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China.
Qinghua ZengDepartment of Oncology, Southern Research Institute, Birmingham, AL, 35205, USA.
Rebecca J BoohakerDepartment of Oncology, Southern Research Institute, Birmingham, AL, 35205, USA.
Joshua FriedDepartment of Oncology, Southern Research Institute, Birmingham, AL, 35205, USA.
Yonghe LiDepartment of Oncology, Southern Research Institute, Birmingham, AL, 35205, USA.
Han WangChongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China.
Bo XuDepartment of Biochemistry and Molecular Biology, The Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. xubo@tmu.edu.cn.

Funding

Beijing-Tianjin-Hebei Basic Research Cooperation Project 19JCZDJC64500(Z)National Natural Science Foundation of China 81974464National Natural Science Foundation of China 82003237
6 · The paper itself

Abstract

backgroundThe activation of the DNA damage response (DDR) heavily relies on post-translational modifications (PTMs) of proteins, which play a crucial role in the prevention of genetic instability and tumorigenesis. Among these PTMs, palmitoylation is a highly conserved process that is dysregulated in numerous cancer types. However, its direct involvement in the DDR and the underlying mechanisms remain unclear.

methodsCRISPR-Cas9 technology was used to generate the PORCN KO and PORCN NLS KO cell lines. The effects of PORCN NLS in the DDR were verified by colony formation assays, MTT assays, the DR/EJ5 homologous recombination/non-homologous end-joining reporter system, xenograft tumor growth and immunofluorescence. Mechanisms were explored by mass spectrometry, acyl-biotin exchange (ABE) palmitoylation assay, Click-iT assay, cell subcellular fractionation assay, Western blot analysis, and in vivo and in vitro co-immunoprecipitation.

resultsIn this study, we introduce evidence that Porcupine (PORCN) is an integral component of and plays a critical role in the DDR. PORCN deficiency hampers nonhomologous end joining (NHEJ) and highly sensitizes cells to ionizing radiation (IR) both in vitro and in vivo. We also provide evidence that PORCN possesses a nuclear fraction (nPORCN) with S-acyltransferase activity, unlike its membrane-bound O-acyltransferase in the endoplasmic reticulum. Furthermore, we show that nPORCN is necessary for the successful activation of NHEJ. Using mass spectrometry, we reveal the existence of an nPORCN complex and show that nPORCN mediates the S-palmitoylation of XRCC6/Ku70 at five specific cysteine sites in response to IR. Mutation of these sites causes a substantial increase in radiosensitivity and delays NHEJ. Additionally, we present evidence that nPORCN-dependent Ku70 palmitoylation is required for DNA-PKcs/Ku70/Ku80 complex formation.

conclusionOur findings underscore the crucial role of nPORCN-dependent Ku70 S-palmitoylation in the DDR.

Indexed as

DNA damage responseKu70Nonhomologous end joining repairPalmitoylationPorcupine

Identifiers

PMID39497152
PMCPMC11536954

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.