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Hypersensitivity to DNA double-strand breaks associated with PARG deficiency is suppressed by exo-1 and polq-1 mutations in Caenorhabditis elegans.
Bae, Woori; Park, Jae Hyung; Lee, Myon-Hee; Park, Hyun Woo; Koo, Hyeon-Sook.
Afiliación
  • Bae W; Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, Korea.
  • Park JH; Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, Korea.
  • Lee MH; Department of Medicine, Hematology/Oncology Division, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
  • Park HW; Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, Korea.
  • Koo HS; Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, Korea.
FEBS J ; 287(6): 1101-1115, 2020 03.
Article en En | MEDLINE | ID: mdl-31593615
Deficiency of either of the two homologs of poly(ADP-ribose) glycohydrolase (PARG), PARG-1 and PARG-2, in Caenorhabditis elegans leads to hypersensitivity to ionizing radiation (IR). In the germ cells of parg-2 mutant worms, the dissipation of recombinase RAD-51 foci was slower than in wild-type (WT) cells, suggesting defects in DNA double-strand break (DSB) repair via homologous recombination (HR). Nevertheless, RPA-1, the large subunit of replication protein A, accumulated faster in parg-2 worms and disappeared earlier than in WT worms. This accelerated RPA-1 accumulation may result from the enhanced expression of exonuclease-1 (EXO-1) after IR treatment. Accordingly, an exo-1 mutation reduced IR sensitivity and accumulation of RPA-1 in parg-2 worms. A mutation of polq-1, encoding for a key factor in the alternative end-joining (Alt-EJ) pathway, suppressed the IR hypersensitivity phenotype of parg-2 worms and normalized the kinetics of RAD-51 dissipation. This indicates that error-prone Alt-EJ may mediate DSB repair in parg-2 worms, causing hypersensitivity to IR. In summary, PARG-2 deficiency in C. elegans causes hyperactive DSB end resection likely through EXO-1 overproduction. DSBs with long single-stranded DNA ends in parg-2 worms are thought to be repaired by Alt-EJ instead of HR, causing genomic instability.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poli(ADP-Ribosa) Polimerasas / Caenorhabditis elegans / ADN Polimerasa Dirigida por ADN / Exodesoxirribonucleasas / Roturas del ADN de Doble Cadena / Mutación Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Revista: FEBS J Asunto de la revista: BIOQUIMICA Año: 2020 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poli(ADP-Ribosa) Polimerasas / Caenorhabditis elegans / ADN Polimerasa Dirigida por ADN / Exodesoxirribonucleasas / Roturas del ADN de Doble Cadena / Mutación Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Revista: FEBS J Asunto de la revista: BIOQUIMICA Año: 2020 Tipo del documento: Article Pais de publicación: Reino Unido