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PARPi monotherapy has shown excellent efficacy and safety profiles in clinical practice but is limited by the need for tumor genome mutations in BRCA or other homologous recombination genes as well as the rapid emergence of resistance. In this study, we identified 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) as a small molecule that selectively kills PARP1- and xeroderma pigmentosum A-deficient cells. CDEAH is a\u00a0monofunctional alkylating agent that preferentially alkylates guanine nucleobases, forming DNA adducts that can be removed from DNA by either a PARP1-dependent base excision repair or nucleotide excision repair. Treatment of PARP1-deficient cells leads to the formation of strand breaks, an accumulation of cells in S phase and activation of the DNA damage response. Furthermore, CDEAH selectively inhibits PARP1-deficient xenograft tumor growth compared to isogenic PARP1-proficient tumors. Collectively, we report the discovery of an alkylating agent inducing DNA damage that requires PARP1 activity for repair and acts synergistically with PARPi.<\/jats:p>","DOI":"10.1093\/narcan\/zcad042","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T11:32:53Z","timestamp":1691407973000},"source":"Crossref","is-referenced-by-count":3,"title":["Alkylation of nucleobases by 2-chloro-<i>N,N<\/i>-diethylethanamine hydrochloride (CDEAH) sensitizes <i>PARP1<\/i>-deficient tumors"],"prefix":"10.1093","volume":"5","author":[{"given":"Minwoo","family":"Wie","sequence":"first","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"},{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology , Ulsan \u00a044919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keon\u00a0Woo","family":"Khim","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"},{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology , Ulsan \u00a044919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold\u00a0S","family":"Groehler\u00a0IV","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soomin","family":"Heo","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"},{"name":"Department of Biomedical Engineering, Ulsan National Institute of Science and Technology , Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhyeok","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ulsan National Institute of Science and Technology , Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kook","family":"Son","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun\u00a0A","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae\u00a0Sun","family":"Ra","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung\u00a0You","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ulsan National Institute of Science and Technology , Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orlando\u00a0D","family":"Sch\u00e4rer","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"},{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology , Ulsan \u00a044919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jang\u00a0Hyun","family":"Choi","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"},{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology , Ulsan \u00a044919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7975-6190","authenticated-orcid":false,"given":"Kyungjae","family":"Myung","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan \u00a044919, Republic of Korea"},{"name":"Department of Biomedical Engineering, Ulsan National Institute of Science and Technology , Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,7]]},"reference":[{"key":"2024032321090978000_B1","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1016\/j.molcel.2022.02.021","article-title":"The expanding universe of PARP1-mediated molecular and therapeutic mechanisms","volume":"82","author":"Huang","year":"2022","journal-title":"Mol. 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