DDX47, MeCP2, and other functionally heterogeneous factors protect cells from harmful R loops.

Cell reports 2023 Mar 28

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Unscheduled R loops can be a source of genome instability, a hallmark of cancer cells. Although targeted proteomic approaches and cellular analysis of specific mutants have uncovered factors potentially involved in R-loop homeostasis, we report a more open screening of factors whose depletion causes R loops based on the ability of activation-induced cytidine deaminase (AID) to target R loops. Immunofluorescence analysis of γH2AX caused by small interfering RNAs (siRNAs) covering 3,205 protein-coding genes identifies 59 potential candidates, from which 13 are analyzed further and show a significant increase of R loops. Such candidates are enriched in factors involved in chromatin, transcription, and RNA biogenesis and other processes. A more focused study shows that the DDX47 helicase is an R-loop resolvase, whereas the MeCP2 methyl-CpG-binding protein uncovers a link between DNA methylation and R loops. Thus, our results suggest that a plethora of gene dysfunctions can alter cell physiology via affecting R-loop homeostasis by different mechanisms. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Esther Marchena-Cruz, Lola P Camino, Jay Bhandari, Sónia Silva, José Javier Marqueta-Gracia, Shahad A Amdeen, Cristina Guillén-Mendoza, María L García-Rubio, José M Calderón-Montaño, Xiaoyu Xue, Rosa Luna, Andrés Aguilera. DDX47, MeCP2, and other functionally heterogeneous factors protect cells from harmful R loops. Cell reports. 2023 Mar 28;42(3):112148