Department of Molecular, Cell and Cancer Biology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Cancer Biology | Cell Biology | Cells | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Female Urogenital Diseases and Pregnancy Complications | Hemic and Lymphatic Diseases | Neoplasms
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 helicase-like transcription factor (HLTF). Correspondingly, HLTF contributes to fork degradation in FANCJ-KO cells. Unexpectedly, the unrestrained DNA synthesis that characterizes HLTF-deficient cells is FANCJ dependent and correlates with S1 nuclease sensitivity and fork degradation. These results suggest that FANCJ and HLTF promote replication fork integrity, in part by counteracting each other to keep fork remodeling and elongation in check. Indicating one protein compensates for loss of the other, loss of both HLTF and FANCJ causes a more severe replication stress response.
DNA replication, FANCJ/BACH1/BRIP1, Fanconi anemia, fork degradation, fork protection, helicase, hereditary breast cancer, iPOND, replication stress response, replisome
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Copyright 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Cell Rep. 2018 Sep 18;24(12):3251-3261. doi: 10.1016/j.celrep.2018.08.065. Link to article on publisher's site
Peng M, Cong K, Panzarino NJ, Nayak S, Calvo J, Deng B, Zhu LJ, Morocz M, Hegedus L, Haracska L, Cantor SB. (2018). Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress. Open Access Publications by UMass Chan Authors. https://doi.org/10.1016/j.celrep.2018.08.065. Retrieved from https://escholarship.umassmed.edu/oapubs/3615
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