{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:17:48Z","timestamp":1792804668812,"version":"4.5.0"},"reference-count":40,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["12075275"],"award-info":[{"award-number":["12075275"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["12135016"],"award-info":[{"award-number":["12135016"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["KFZC2021010401"],"award-info":[{"award-number":["KFZC2021010401"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["YZJJZX202014"],"award-info":[{"award-number":["YZJJZX202014"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["XDA17010502"],"award-info":[{"award-number":["XDA17010502"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["HIR2021PY014"],"award-info":[{"award-number":["HIR2021PY014"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Innovative Center of Radiation Application","award":["12075275"],"award-info":[{"award-number":["12075275"]}]},{"name":"Innovative Center of Radiation Application","award":["12135016"],"award-info":[{"award-number":["12135016"]}]},{"name":"Innovative Center of Radiation Application","award":["KFZC2021010401"],"award-info":[{"award-number":["KFZC2021010401"]}]},{"name":"Innovative Center of Radiation Application","award":["YZJJZX202014"],"award-info":[{"award-number":["YZJJZX202014"]}]},{"name":"Innovative Center of Radiation Application","award":["XDA17010502"],"award-info":[{"award-number":["XDA17010502"]}]},{"name":"Innovative Center of Radiation Application","award":["HIR2021PY014"],"award-info":[{"award-number":["HIR2021PY014"]}]},{"name":"Hefei Institute of Physical Science","award":["12075275"],"award-info":[{"award-number":["12075275"]}],"id":[{"id":"https:\/\/ror.org\/046n57345","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Hefei Institute of Physical Science","award":["12135016"],"award-info":[{"award-number":["12135016"]}],"id":[{"id":"https:\/\/ror.org\/046n57345","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Hefei Institute of Physical Science","award":["KFZC2021010401"],"award-info":[{"award-number":["KFZC2021010401"]}],"id":[{"id":"https:\/\/ror.org\/046n57345","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Hefei Institute of Physical Science","award":["YZJJZX202014"],"award-info":[{"award-number":["YZJJZX202014"]}],"id":[{"id":"https:\/\/ror.org\/046n57345","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Hefei Institute of Physical Science","award":["XDA17010502"],"award-info":[{"award-number":["XDA17010502"]}],"id":[{"id":"https:\/\/ror.org\/046n57345","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Hefei Institute of Physical Science","award":["HIR2021PY014"],"award-info":[{"award-number":["HIR2021PY014"]}],"id":[{"id":"https:\/\/ror.org\/046n57345","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Chinese Academy of Sciences","award":["12075275"],"award-info":[{"award-number":["12075275"]}],"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Chinese Academy of Sciences","award":["12135016"],"award-info":[{"award-number":["12135016"]}],"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Chinese Academy of Sciences","award":["KFZC2021010401"],"award-info":[{"award-number":["KFZC2021010401"]}],"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Chinese Academy of Sciences","award":["YZJJZX202014"],"award-info":[{"award-number":["YZJJZX202014"]}],"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Chinese Academy of Sciences","award":["XDA17010502"],"award-info":[{"award-number":["XDA17010502"]}],"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Chinese Academy of Sciences","award":["HIR2021PY014"],"award-info":[{"award-number":["HIR2021PY014"]}],"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Heavy Ion Research Facility in Lanzhou","award":["12075275"],"award-info":[{"award-number":["12075275"]}]},{"name":"Heavy Ion Research Facility in Lanzhou","award":["12135016"],"award-info":[{"award-number":["12135016"]}]},{"name":"Heavy Ion Research Facility in Lanzhou","award":["KFZC2021010401"],"award-info":[{"award-number":["KFZC2021010401"]}]},{"name":"Heavy Ion Research Facility in Lanzhou","award":["YZJJZX202014"],"award-info":[{"award-number":["YZJJZX202014"]}]},{"name":"Heavy Ion Research Facility in Lanzhou","award":["XDA17010502"],"award-info":[{"award-number":["XDA17010502"]}]},{"name":"Heavy Ion Research Facility in Lanzhou","award":["HIR2021PY014"],"award-info":[{"award-number":["HIR2021PY014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Life has evolved a mechanism called DNA damage response (DDR) to sense, signal and remove\/repair DNA damage, and its deficiency and dysfunction usually lead to genomic instability and development of cancer. The signaling mode of the DDR has been believed to be of cell-autonomy. However, the paradigm is being shifted with in-depth research into model organism Caenorhabditis elegans. Here, we mainly investigate the effect of DDR activation on the radiosensitivity of vulva of C. elegans, and first found that the vulval radiosensitivity is mainly regulated by somatic DDR, rather than the DDR of germline. Subsequently, the worm lines with pharynx-specific rescue of DDR were constructed, and it is shown that the 9-1-1-ATR and MRN-ATM cascades in pharynx restore approximately 90% and 70% of vulval radiosensitivity, respectively, through distantly regulating the NHEJ repair of vulval cells. The results suggest that the signaling cascade of DDR might also operate in a non-cell autonomous mode. To further explore the underlying regulatory mechanisms, the cpr-4 mutated gene is introduced into the DDR-rescued worms, and CPR-4, a cysteine protease cathepsin B, is confirmed to mediate the inter-tissue and inter-individual regulation of DDR as a signaling molecule downstream of 9-1-1-ATR. Our findings throw some light on the regulation of DNA repair in soma of C. elegans, and might also provide new cues for cancer prevention and treatment.<\/jats:p>","DOI":"10.3390\/ijms23147544","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T22:11:47Z","timestamp":1657231907000},"page":"7544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Non-Cell-Autonomous Mode of DNA Damage Response in Soma of Caenorhabditis elegans"],"prefix":"10.3390","volume":"23","author":[{"given":"Zhangyu","family":"Dai","sequence":"first","affiliation":[{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China"},{"name":"Science Island Branch of Graduate School, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China"},{"name":"Science Island Branch of Graduate School, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengke","family":"Shang","sequence":"additional","affiliation":[{"name":"Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huangqi","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuejin","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4839-6329","authenticated-orcid":false,"given":"Ting","family":"Wang","sequence":"additional","affiliation":[{"name":"Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2581-9317","authenticated-orcid":false,"given":"Po","family":"Bian","sequence":"additional","affiliation":[{"name":"Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China"},{"name":"Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA damage response: Making it safe to play with knives","volume":"40","author":"Ciccia","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","article-title":"ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response","volume":"66","author":"Blackford","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"Jackson","year":"2009","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41568-021-00386-6","article-title":"Targeting the DNA damage response in immuno-oncology: Developments and opportunities","volume":"21","author":"Chabanon","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1101\/gad.348314.121","article-title":"Interfaces between cellular responses to DNA damage and cancer immunotherapy","volume":"35","author":"Pilger","year":"2021","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41467-022-28225-8","article-title":"Somatic PMK-1\/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy","volume":"13","author":"Soltanmohammadi","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1667\/RR3218.1","article-title":"Radiation-induced bystander signaling from somatic cells to germ cells in Caenorhabditis elegans","volume":"180","author":"Guo","year":"2013","journal-title":"Radiat. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/nature23284","article-title":"Cysteine protease cathepsin B mediates radiation-induced bystander effects","volume":"547","author":"Peng","year":"2017","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature09141","article-title":"HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase","volume":"465","author":"Sendoel","year":"2010","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.devcel.2019.06.012","article-title":"Somatic niche cells regulate the CEP-1\/p53-mediated DNA damage response in primordial germ cells","volume":"50","author":"Ou","year":"2019","journal-title":"Dev. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.1158\/0008-5472.CAN-06-4442","article-title":"DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models","volume":"67","author":"Sedelnikova","year":"2007","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7257","DOI":"10.1038\/sj.onc.1208886","article-title":"Ionizing radiation induces DNA double-strand breaks in bystander primary human fibroblasts","volume":"24","author":"Sokolov","year":"2005","journal-title":"Oncogene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.dnarep.2015.04.025","article-title":"Tissue specific response to DNA damage: C. elegans as role model","volume":"32","author":"Lans","year":"2015","journal-title":"DNA Repair."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1038\/cdd.2012.69","article-title":"Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans","volume":"19","author":"Vermezovic","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3389\/fcell.2020.00041","article-title":"Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer","volume":"8","author":"Sia","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1667\/RR13855.1","article-title":"Induction and Repair of DNA DSB as Revealed by H2AX Phosphorylation Foci in Human Fibroblasts Exposed to Low- and High-LET Radiation: Relationship with Early and Delayed Reproductive Cell Death","volume":"183","author":"Antonelli","year":"2015","journal-title":"Radiat. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9946","DOI":"10.1073\/pnas.0603791103","article-title":"A Caenorhabditis elegans tissue model of radiation-induced reproductive cell death","volume":"103","author":"Weidhaas","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1667\/RR14368.1","article-title":"Radioadaptive response for reproductive cell death demonstrated in in vivo tissue model of Caenorhabditis elegans","volume":"185","author":"Tang","year":"2016","journal-title":"Radiat. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.dnarep.2018.01.009","article-title":"Induction of reproductive cell death in Caenorhabditis elegans across entire linear-energy-transfer range of carbon-ion irradiation","volume":"63","author":"Chen","year":"2018","journal-title":"DNA Repair."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1667\/RR14548.1","article-title":"Interaction between radioadaptive response and radiation-induced bystander effect in Caenorhabditis elegans: A unique role of the DNA damage checkpoint","volume":"186","author":"Tang","year":"2016","journal-title":"Radiat. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/0092-8674(87)90128-0","article-title":"glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans","volume":"51","author":"Austin","year":"1987","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1534\/g3.113.005785","article-title":"Resistance to germline RNA interference in a Caenorhabditis elegans wild isolate exhibits complexity and nonadditivity","volume":"3","author":"Pollard","year":"2013","journal-title":"G3 Genes Genomes Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1242\/dev.02241","article-title":"The C. elegans Myt1 ortholog is required for the proper timing of oocyte maturation","volume":"133","author":"Burrows","year":"2006","journal-title":"Development"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1038\/s41422-019-0247-3","article-title":"Cathepsin B inhibitors block multiple radiation-induced side effects in C. elegans","volume":"29","author":"Zheng","year":"2019","journal-title":"Cell Res."},{"key":"ref_26","first-page":"8193892","article-title":"DNA damage as a driver for growth delay: Chromosome instability syndromes with intrauterine growth retardation","volume":"2017","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_27","first-page":"e4019","article-title":"Basic Caenorhabditis elegans methods: Synchronization and observation","volume":"64","author":"Fontrodona","year":"2012","journal-title":"JoVE (J. Vis. Exp.)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1073\/pnas.83.8.2305","article-title":"Immunological identification of the genes encoding the four myosin heavy chain isoforms of Caenorhabditis elegans","volume":"83","author":"Miller","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Mango, S.E. (2007). The C. elegans pharynx: A model for organogenesis. WormBook: The Online Review of C. elegans Biology, National Laboratory of Medicine.","DOI":"10.1895\/wormbook.1.129.1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/nature12452","article-title":"DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance","volume":"501","author":"Ermolaeva","year":"2013","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17905","DOI":"10.1073\/pnas.1420439111","article-title":"Communication between oocytes and somatic cells regulates volatile pheromone production in Caenorhabditis elegans","volume":"111","author":"Leighton","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"a012724","DOI":"10.1101\/cshperspect.a012724","article-title":"DNA damage response: Three levels of DNA repair regulation","volume":"5","author":"Sirbu","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_33","first-page":"32355263","article-title":"DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer","volume":"5","author":"Huang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Vitti, E.T., and Parsons, J.L. (2019). The Radiobiological Effects of Proton Beam Therapy: Impact on DNA Damage and Repair. Cancers, 11.","DOI":"10.3390\/cancers11070946"},{"key":"ref_35","first-page":"32","article-title":"Effect of heterogeneous radio sensitivity on the survival, alpha beta ratio and biologic effective dose calculation of irradiated mammalian cell populations","volume":"4","author":"Hawkins","year":"2017","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","article-title":"The genetics of Caenorhabditis elegans","volume":"77","author":"Brenner","year":"1974","journal-title":"Genetics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1091\/mbc.3.11.1199","article-title":"Molecular basis of loss-of-function mutations in the glp-1 gene of Caenorhabditis elegans","volume":"3","author":"Kodoyianni","year":"1992","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","first-page":"RESEARCH0002","article-title":"Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans","volume":"2","author":"Kamath","year":"2001","journal-title":"Genome Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1016\/j.celrep.2018.04.072","article-title":"A cytoplasmic argonaute protein promotes the inheritance of RNAi","volume":"23","author":"Xu","year":"2018","journal-title":"Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/nature03353","article-title":"Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans","volume":"434","author":"Koski","year":"2005","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7544\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:44:09Z","timestamp":1760139849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,7]]},"references-count":40,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147544"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147544","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,7]]}}}