RAD54L coordinates the nucleolar DNA damage response to maintain rDNA stability
- Author(s)
- Liu, R; Xuan, J; Cerra, C; Stojnic, N; Pan, J; Chelliah, SS; Mendez, S; Dmello, R; Cowley, KJ; Zhang, Y; Gitareja, K; Wakefield, M; Deans, A; Scott, CL; Chan, KT; Simpson, KJ; Kang, J; Sanij, E;
- Journal Title
- EMBO Journal
- Publication Type
- Jul 23
- Abstract
- The nucleolus is organized around actively transcribed ribosomal RNA genes (rDNA), where high RNA polymerase I (Pol I) activity creates intrinsic susceptibility to replication stress and DNA damage. Here, we identify the DNA translocase RAD54L as a critical regulator of the nucleolar DNA damage response (nDDR) to rDNA double-strand breaks (DSBs) and replication stress. We show that RAD54L localizes to the nucleolus under basal conditions and is recruited to nucleolar caps following CRISPR-Cas9-induced rDNA-DSBs to promote repair. RAD54L loss results in persistent RAD51 foci, increased nucleolar γH2AX, and micronuclei formation, indicating defective resolution of rDNA lesions and genome instability. Under baseline conditions and replication stress induced by the Pol I transcription inhibitor CX-5461, RAD54L limits the accumulation of ssDNA and coordinates nDDR signaling. We further show that rDNA-DSBs induce RNA polymerase II-dependent RNA-DNA hybrids (R-loops) at intergenic rDNA regions, which facilitate nucleolar reorganization and cap formation and repair factor recruitment. Together, these findings establish RAD54L as a key regulator that coordinates replication stress response and rDNA repair, maintaining rDNA stability and genome integrity.
- Publisher
- Springer
- Research Division(s)
- Bioinformatics and Computational Biology; Cancer Biology and Stem Cells
- PubMed ID
- 42493648
- Publisher's Version
- https://doi.org/10.1038/s44318-026-00864-3
- Open Access at Publisher's Site
https://doi.org/10.1038/s44318-026-00864-3- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-07-30 09:25:12
Last Modified: 2026-07-30 09:25:28