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bioRxiv · 10.1101/2025.04.15.648866

The FANCD2-FANCI heterodimer coordinates chromatin openness and cell cycle progression throughout DNA double-strand break repair.

Joyce, C. M.·Bacal, J.·Chowdhury, S. P.·Brown, A. N.·Wang, A. K.·Cruz, C.·Bains, K.·Rodriguez, Z. N.·McCormick, N. J.·Tzadikario, Y.·Tavasoli, K. U.·Gardner, B. M.·Richardson, C. D.
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Abstract

The FANCD2-FANCI heterodimer contributes to DNA repair at interstrand crosslinks and sites of replication stress. This complex has been physically and mechanistically linked to double-strand break (DSB) repair, but its role in that process remains undefined. Here we show that the FANCD2-FANCI heterodimer dynamically interacts with open chromatin regions, including transient, DSB-induced open chromatin, where it can be stabilized by co-activation by the DNA repair kinase ATM and the Fanconi anemia core ubiquitin ligase. The loaded FANCD2-FANCI heterodimer stabilizes open chromatin and promotes resection and loading of RPA through increased association of BRCA1 and BLM. Chromatin-loaded FANCD2-FANCI has a second distinct function promoting a G2 arrest that is dependent on the ATR-CHK1-WEE1 axis. Our results support a two-step genome surveillance model in which FANCD2-FANCI monitors open chromatin sites and is stably loaded to coordinate DNA repair activities in response to signaling from a DNA repair kinase.

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Joyce, C. M., Bacal, J., Chowdhury, S. P., Brown, A. N., Wang, A. K., Cruz, C., Bains, K., Rodriguez, Z. N., McCormick, N. J., Tzadikario, Y., Tavasoli, K. U., Gardner, B. M., Richardson, C. D.. 2025-04-16. The FANCD2-FANCI heterodimer coordinates chromatin openness and cell cycle progression throughout DNA double-strand break repair.. https://doi.org/10.1101/2025.04.15.648866

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