{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T01:24:42Z","timestamp":1768699482315,"version":"3.49.0"},"reference-count":86,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T00:00:00Z","timestamp":1604534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes\u2019 assembly. Nuclear PAR affects chromatin\u2019s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1\/2), base excision repair proteins (XRCC1, Pol\u03b2), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.<\/jats:p>","DOI":"10.3390\/ijms21218288","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T09:04:34Z","timestamp":1604567074000},"page":"8288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors"],"prefix":"10.3390","volume":"21","author":[{"given":"Valentina","family":"Perini","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Biol\u00f3gicas Clemente Estable (IIBCE), Departamento de Gen\u00e9tica,   Montevideo 11.600, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Schacke","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biol\u00f3gicas Clemente Estable (IIBCE), Departamento de Gen\u00e9tica,   Montevideo 11.600, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Liddle","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biol\u00f3gicas Clemente Estable (IIBCE), Departamento de Gen\u00e9tica,   Montevideo 11.600, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8302-1509","authenticated-orcid":false,"given":"Salom\u00e9","family":"Vilchez-Larrea","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones en Ingenier\u00eda Gen\u00e9tica y Biolog\u00eda Molecular \u201cDr. H\u00e9ctor N. Torres\u201d, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Ciudad Aut\u00f3noma de Buenos Aires 1428, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah J.","family":"Keszenman","sequence":"additional","affiliation":[{"name":"Laboratorio de Radiobiolog\u00eda M\u00e9dica y Ambiental, Grupo de Biofisicoqu\u00edmica, Centro Universitario Regional Litoral Norte, Universidad de la Rep\u00fablica (UdelaR), Salto 50.000, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4239-2802","authenticated-orcid":false,"given":"Laura","family":"Lafon-Hughes","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biol\u00f3gicas Clemente Estable (IIBCE), Departamento de Gen\u00e9tica,   Montevideo 11.600, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1093\/nar\/gkv1383","article-title":"Survey and summary readers of poly(ADP-ribose): Designed to be fit for purpose","volume":"44","author":"Teloni","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1006975002262","article-title":"Poly ADP-ribosylation: A DNA break signal mechanism","volume":"193","author":"Althaus","year":"1999","journal-title":"Proc. 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