Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress

• Main Authors: Min Peng, Ke Cong, Nicholas J. Panzarino, Sumeet Nayak, Jennifer Calvo, Bin Deng, Lihua Julie Zhu, Monika Morocz, Lili Hegedus, Lajos Haracska, Sharon B. Cantor
• Format: Article
• Language: English
• Published: Elsevier 2018-09-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112471831369X

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 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. : Peng et al. find that loss of FANCJ enhances the replisome association of helicase-like transcription factor (HLTF). HLTF depletion suppresses fork degradation in FANCJ-deficient cells, and FANCJ depletion suppresses aberrant fork elongation in HLTF-deficient cells. However, the combined loss of HLTF and FANCJ causes severe replication stress. Keywords: FANCJ/BACH1/BRIP1, Fanconi anemia, hereditary breast cancer, DNA replication, replication stress response, helicase, replisome, fork protection, fork degradation, iPOND