Michelle N. Yancoskie

The three-dimensional (3D) genome architecture is highly elastic, adapting to nuclear processes such as transcription and the DNA damage response (Dekker & Mirny 2016; Carré-Simon & Fabre 2021). Nucleotide excision repair (NER) acts within this chromatin context to detect and repair mutagenic lesions induced by ultraviolet (UV) irradiation (Sancar 2016). UV irradiation has been shown to induce restructuring of the 3D genome across multiple scales, including chromatin compartments, domains, and loops. However, the extent to which NER activity contributes to this remodelling is unresolved, as the only prior study tracking such UV-induced changes was limited to repair-proficient cells (Kaya & Adebali 2025). Here, by combining genome-wide chromatin profiling of repair-deficient human cells with loop extrusion simulations, we show that lesion-stalled RNA polymerase II (RNAPII) and repair-associated barriers constrain loop extrusion. These events counter the loop-lengthening effects of UV-induced transcriptional shutdown, leading to shorter chromatin loops and reinforced chromatin domains that facilitate efficient lesion recognition and repair. The contribution by NER machinery underscores 3D genome reorganisation as an active mechanism both initiated and harnessed by DNA repair, rather than a passive consequence of DNA damage. The contribution by RNAPII extends its role beyond activating transcription-coupled repair to promoting a genome-wide repair-permissive state. Together, these findings advance our understanding of how nuclear processes coordinate on a shared chromatin substrate to preserve genome integrity.

The mammalian genome is hierarchically structured to maintain accessibility and flexibility for essential nuclear processes such as transcription and DNA repair. A recent study using high-throughput 3D genome mapping reveals that nucleotide excision repair triggers large-scale chromatin rearrangements, reinforcing topologically associating domains and chromatin compartments. Notably, similar principles of chromatin stabilization are observed during double-strand break repair, consistent with the notion that chromatin restructuring may be an active and conserved DNA repair strategy rather than a passive consequence of damage. The observed stabilization is postulated to optimize repair efficiency by reducing the search space for damage, enhancing DNA accessibility at damage sites, increasing local concentrations of repair factors, and preventing aberrant chromosomal rearrangements. By synthesizing emerging evidence on nucleotide excision repair–driven chromatin dynamics and its parallels with double-strand break repair, this review examines how genome architecture actively shapes the DNA damage response and highlights broader implications for genetic diseases and therapeutic strategies.

The histone methyltransferase ASH1L, first discovered for its role in transcription, has been shown to accelerate the removal of ultraviolet (UV) light-induced cyclobutane pyrimidine dimers (CPDs) by nucleotide excision repair. Previous reports demonstrated that CPD excision is most efficient at transcriptional regulatory elements, including enhancers, relative to other genomic sites. Therefore, we analyzed DNA damage maps in ASH1L-proficient and ASH1L-deficient cells to understand how ASH1L controls enhancer stability. This comparison showed that ASH1L protects enhancer sequences against the induction of CPDs besides stimulating repair activity. ASH1L reduces CPD formation at C–containing but not at TT dinucleotides, and no protection occurs against pyrimidine-(6,4)-pyrimidone photoproducts or cisplatin crosslinks. The diminished CPD induction extends to gene promoters but excludes retrotransposons. This guardian role against CPDs in regulatory elements is associated with the presence of H3K4me3 and H3K27ac histone marks, which are known to interact with the PHD and BRD motifs of ASH1L, respectively. Molecular dynamics simulations identified a DNA-binding AT hook of ASH1L that alters the distance and dihedral angle between neighboring C nucleotides to disfavor dimerization. The loss of this protection results in a higher frequency of C–>T transitions at enhancers of skin cancers carrying ASH1L mutations compared to ASH1L-intact counterparts.

To recognize DNA adducts, nucleotide excision repair (NER) deploys the XPC sensor, which detects damage-induced helical distortions, followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place in chromatin where DNA is tightly wrapped around histones. Here, we describe how the histone methyltransferase ASH1L, once activated by MRG15, helps XPC and TFIIH to navigate through chromatin and induce global-genome NER hotspots. Upon UV irradiation, ASH1L adds H3K4me3 all over the genome (except in active gene promoters), thus priming chromatin for XPC relocations from native to damaged DNA. The ASH1L-MRG15 complex further recruits the histone chaperone FACT to DNA lesions. In the absence of ASH1L, MRG15 or FACT, XPC is misplaced and persists on damaged DNA without being able to deliver the lesions to TFIIH. We conclude that ASH1L-MRG15 makes damage verifiable by the NER machinery through the sequential deposition of H3K4me3 and FACT.