2018
DOI: 10.1016/j.celrep.2018.08.065
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Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress

Abstract: SUMMARY The DNA helicase FANCJ is mutated in hereditary breast and ovarian cancer and Fanconi anemia (FA). Nevertheless, how loss of FANCJ translates to disease pathogenesis remains unclear. We addressed this question by analyzing proteins associated with replication forks in cells with or without FANCJ. We demonstrate that FANCJ-knockout (FANCJ-KO) cells have alterations in the replisome that are consistent with enhanced replication stress, including an aberrant accumulation of the fork remodeling factor heli… Show more

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Cited by 64 publications
(74 citation statements)
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“…Here, we employed the FANCJ interaction defective BRCA1 mutant, FANCJ S990A , that promotes TLS via the polymerase polh (Xie et al, 2010a). We complemented FANCJ K/O U2OS, osteosarcoma cancer cells and FANCJ-null FA-J patient immortalized fibroblast cells, with FANCJ S990A (pro-TLS), FANCJ WT (control), or vector (V) and found as expected that both FANCJ WT and FANCJ S990A elevated mitomycin C (MMC) or cisplatin resistance as compared to vector (Figure 1B, S1A and S1B) (Peng et al, 2018;Xie et al, 2010a). In order to track the actively replicating fork, cells were labeled with sequential pulses of iodo-2′-deoxyuridine (IdU) and 5-chloro-2′-deoxyuridine (CldU) and the DNA tract lengths were measured.…”
Section: Tls Limits Replication Fork Slowing During Stresssupporting
confidence: 59%
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“…Here, we employed the FANCJ interaction defective BRCA1 mutant, FANCJ S990A , that promotes TLS via the polymerase polh (Xie et al, 2010a). We complemented FANCJ K/O U2OS, osteosarcoma cancer cells and FANCJ-null FA-J patient immortalized fibroblast cells, with FANCJ S990A (pro-TLS), FANCJ WT (control), or vector (V) and found as expected that both FANCJ WT and FANCJ S990A elevated mitomycin C (MMC) or cisplatin resistance as compared to vector (Figure 1B, S1A and S1B) (Peng et al, 2018;Xie et al, 2010a). In order to track the actively replicating fork, cells were labeled with sequential pulses of iodo-2′-deoxyuridine (IdU) and 5-chloro-2′-deoxyuridine (CldU) and the DNA tract lengths were measured.…”
Section: Tls Limits Replication Fork Slowing During Stresssupporting
confidence: 59%
“…Additionally, in fork degradation-prone BRCA2-deficient PEO1 ovarian cancer cells (Sakai et al, 2009) (Kolinjivadi et al, 2017;Mijic et al, 2017;Schlacher et al, 2011;Taglialatela et al, 2017), ectopic expression of the pro-TLS mutant not only enhanced fork protection, but also conferred cisplatin resistance as forks failed to fully slow as compared to control (Figure 1F and S1H). Taken together, these findings indicate that TLS provides fork protection through suppression of fork remodeling similar to the loss of fork remodelers (Kolinjivadi et al, 2017;Peng et al, 2018;Vujanovic et al, 2017).…”
Section: Tls Avoids Fork Reversal and Degradationmentioning
confidence: 72%
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“…Peptides were injected into the mass spectrometer via a nanospray ionization source at a spray voltage of 2.2 kV. The mass spectrometer was operated in a data-dependent fashion using a top-10 mode (Peng et al, 2018).…”
Section: Proteomicsmentioning
confidence: 99%