FANCI and FANCD2 have common as well as independent functions during the cellular replication stress response

Elizabeth L. Thompson, Jung E. Yeo, Eun A. Lee, Yinan Kan, Maya Raghunandan, Constanze Wiek, Helmut Hanenberg, Orlando D. Schärer, Eric A. Hendrickson, Alexandra Sobeck

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9 Scopus citations

Abstract

Fanconi anemia (FA) is an inherited cancer predisposition syndrome characterized by cellular hypersensitivity to DNA interstrand crosslinks (ICLs). To repair these lesions, the FA proteins act in a linear hierarchy: following ICL detection on chromatin, the FA core complex monoubiquitinates and recruits the central FANCI and FANCD2 proteins that subsequently coordinate ICL removal and repair of the ensuing DNA double-stranded break by homology-dependent repair (HDR). FANCD2 also functions during the replication stress response by mediating the restart of temporarily stalled replication forks thereby suppressing the firing of new replication origins. To address if FANCI is also involved in these FANCD2-dependent mechanisms, we generated isogenic FANCI-, FANCD2- and FANCI:FANCD2 double-null cells. We show that FANCI and FANCD2 are partially independent regarding their protein stability, nuclear localization and chromatin recruitment and contribute independently to cellular proliferation. Simultaneously, FANCD2––but not FANCI––plays a major role in HDR-mediated replication restart and in suppressing new origin firing. Consistent with this observation, deficiencies in HDR-mediated DNA DSB repair can be overcome by stabilizing RAD51 filament formation in cells lacking functional FANCD2. We propose that FANCI and FANCD2 have partially non-overlapping and possibly even opposing roles during the replication stress response.

Original languageEnglish (US)
Pages (from-to)11837-11857
Number of pages21
JournalNucleic acids research
Volume45
Issue number20
DOIs
StatePublished - 2017

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    Thompson, E. L., Yeo, J. E., Lee, E. A., Kan, Y., Raghunandan, M., Wiek, C., Hanenberg, H., Schärer, O. D., Hendrickson, E. A., & Sobeck, A. (2017). FANCI and FANCD2 have common as well as independent functions during the cellular replication stress response. Nucleic acids research, 45(20), 11837-11857. https://doi.org/10.1093/nar/gkx847