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Error-prone repair of stalled replication forks drives mutagenesis and loss of heterozygosity in haploinsufficient BRCA1 cells.
Deshpande, Madhura; Paniza, Theodore; Jalloul, Nahed; Nanjangud, Gouri; Twarowski, Jerzy; Koren, Amnon; Zaninovic, Nikica; Zhan, Qiansheng; Chadalavada, Kalyani; Malkova, Anna; Khiabanian, Hossein; Madireddy, Advaitha; Rosenwaks, Zev; Gerhardt, Jeannine.
Afiliación
  • Deshpande M; The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • Paniza T; The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • Jalloul N; Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA.
  • Nanjangud G; Molecular Cytogenetics Core Facility, Sloan Kettering Institute, New York, NY 10065, USA.
  • Twarowski J; Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
  • Koren A; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA.
  • Zaninovic N; The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • Zhan Q; The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • Chadalavada K; Molecular Cytogenetics Core Facility, Sloan Kettering Institute, New York, NY 10065, USA.
  • Malkova A; Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
  • Khiabanian H; Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA.
  • Madireddy A; Department of Pediatric Hematology/Oncology, Rutgers University, New Brunswick, NJ 08903, USA.
  • Rosenwaks Z; The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • Gerhardt J; The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: jeg2039@med.cornell.edu.
Mol Cell ; 82(20): 3781-3793.e7, 2022 10 20.
Article en En | MEDLINE | ID: mdl-36099913
Germline mutations in the BRCA genes are associated with a higher risk of carcinogenesis, which is linked to an increased mutation rate and loss of the second unaffected BRCA allele (loss of heterozygosity, LOH). However, the mechanisms triggering mutagenesis are not clearly understood. The BRCA genes contain high numbers of repetitive DNA sequences. We detected replication forks stalling, DNA breaks, and deletions at these sites in haploinsufficient BRCA cells, thus identifying the BRCA genes as fragile sites. Next, we found that stalled forks are repaired by error-prone pathways, such as microhomology-mediated break-induced replication (MMBIR) in haploinsufficient BRCA1 breast epithelial cells. We detected MMBIR mutations in BRCA1 tumor cells and noticed deletions-insertions (>50 bp) at the BRCA1 genes in BRCA1 patients. Altogether, these results suggest that under stress, error-prone repair of stalled forks is upregulated and induces mutations, including complex genomic rearrangements at the BRCA genes (LOH), in haploinsufficient BRCA1 cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína BRCA1 / Replicación del ADN Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína BRCA1 / Replicación del ADN Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos