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

Peng, Min and Cong, Ke and Panzarino, Nicholas J. and Nayak, Sumeet and Calvo, Jennifer and Mórocz, Mónika and Hegedűs, Lili and Haracska, Lajos (2018) Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress. CELL REPORTS, 24 (12). pp. 3251-3261. ISSN 2639-1856 (print); 2211-1247 (online)

Preview

Text PengCellRep2018.pdf Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (2MB) | Preview

Abstract

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.

Actions (login required)

Edit Item