Nature Structural & Molecular Biology · 7 authors, 3 centres
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The DREAM repressor complex limits DNA-repair capacity in somatic cells by transcriptionally repressing multiple DNA-repair genes. Mutations or pharmacological inhibition of DREAM boost DNA-damage resistance in C. elegans, human cells, and progeroid mice, reducing photoreceptor loss. This reveals a conserved master regulator that could be targeted to treat DNA-repair deficiencies and age-related diseases.
**Background:** DNA-repair capacity is high in germ cells but limited in somatic cells, contributing to age-dependent mutation accumulation and degenerative diseases. The DREAM complex (Dp/Rb-like/E2F + MuvB) controls cellular quiescence and differentiation, but its role in regulating overall DNA repair was unknown. This study investigates whether DREAM represses DNA-repair genes in somatic tissues and whether its inhibition can boost repair across species.
**Methods:** The authors used C. elegans mutants lacking DREAM components (lin-52, dpl-1, efl-1, lin-35, lin-53) and assessed developmental growth, lifespan, and DNA-lesion removal (CPDs, 6-4PPs) after UV, ionizing radiation (IR), methyl methanesulfonate (MMS), and cisplatin. RNA-seq, proteomics, and ChIP–seq re-analysis identified DREAM-bound DDR genes. In human U2OS cells, DYRK1A inhibitors harmine and INDY were used to disrupt DREAM assembly; apoptosis was measured by annexin V/7-AAD after UV or MMS. In vivo, Ercc1−/− progeroid mice were treated with harmine (10 mg/kg i.p., 3×/week from P3 to P15), and retinal photoreceptor loss (TUNEL) and DNA damage (γH2AX) were quantified.
**Key Results:** In C. elegans, DREAM mutants showed significantly improved somatic development after UV (e.g., lin-52 mutants progressed through larval stages faster than WT at high UV doses) and extended lifespan upon UV (e.g., lin-52 mean lifespan decreased only 8% vs. 28% in WT). CPD removal was enhanced in lin-52 and dpl-1 mutants (e.g., lin-52 showed ~40% improved repair vs. WT at 24 h). DREAM mutations suppressed UV sensitivity of csb-1 and xpc-1 single mutants but not xpa-1 or csb-1;xpc-1 double mutants, indicating dependence on NER. RNA-seq revealed 53 DDR genes significantly upregulated in lin-52 mutants (adjusted P < 0.05), including NER, BER, HRR, NHEJ, ICL, and MMR genes; 41 of these were directly bound by DREAM in ChIP–seq. Proteomics confirmed upregulation of multiple DDR proteins. DREAM mutants also resisted IR (e.g., lin-52 embryos had ~80% hatching vs. ~50% in WT at 60 Gy), MMS, and cisplatin. In human U2OS cells, harmine and INDY upregulated DREAM-targeted DDR genes (58 and 46 of 67 DNA-repair genes, respectively) and significantly reduced apoptosis after UV (e.g., harmine: ~15% vs. ~35% annexin V+ in mock) and MMS. In Ercc1−/− mice, harmine treatment significantly reduced TUNEL-positive cells in the outer nuclear layer (ONL) and decreased γH2AX signal in the inner nuclear layer (INL) compared to untreated Ercc1−/− mice.
**Clinical Implications:** The DREAM complex is a conserved master repressor of somatic DNA-repair capacities. Pharmacological inhibition of DREAM (via DYRK1A inhibitors) could provide a novel therapeutic strategy for congenital DNA-repair deficiency syndromes (e.g., Cockayne syndrome, xeroderma pigmentosum) and age-related degenerative conditions driven by DNA damage. The study demonstrates that boosting multiple repair pathways simultaneously can compensate for single-pathway defects, offering a broad approach to enhance genome stability.