Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance
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Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance. / Classen, Sandra; Rahlf, Elena; Jungwirth, Johannes; Albers, Nina; Hebestreit, Luca Philipp; Zielinski, Alexandra; Poole, Lena; Groth, Marco; Koch, Philipp; Liehr, Thomas; Kankel, Stefanie; Cordes, Nils; Petersen, Cordula; Rothkamm, Kai; Pospiech, Helmut; Borgmann, Kerstin.
in: INT J MOL SCI, Jahrgang 23, Nr. 21, 13363, 01.11.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance
AU - Classen, Sandra
AU - Rahlf, Elena
AU - Jungwirth, Johannes
AU - Albers, Nina
AU - Hebestreit, Luca Philipp
AU - Zielinski, Alexandra
AU - Poole, Lena
AU - Groth, Marco
AU - Koch, Philipp
AU - Liehr, Thomas
AU - Kankel, Stefanie
AU - Cordes, Nils
AU - Petersen, Cordula
AU - Rothkamm, Kai
AU - Pospiech, Helmut
AU - Borgmann, Kerstin
N1 - E Rahlf, N Albers und LP Hebestreit bitte als interne Autoren mit Affiliation "Klinik für Strahlentherapie" eintragen.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.
AB - BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.
KW - Humans
KW - Female
KW - Genes, BRCA1
KW - Cell Line, Tumor
KW - BRCA1 Protein/genetics
KW - Homologous Recombination
KW - DNA Repair/genetics
KW - DNA Replication
KW - DNA Damage
KW - Breast Neoplasms/genetics
U2 - 10.3390/ijms232113363
DO - 10.3390/ijms232113363
M3 - SCORING: Journal article
C2 - 36362151
VL - 23
JO - INT J MOL SCI
JF - INT J MOL SCI
SN - 1661-6596
IS - 21
M1 - 13363
ER -