DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. The swift recognition and faithful repair of such damage is crucial for the maintenance of genomic stability, as well as for cell and organismal fitness. Signalling by ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs) orchestrates and regulates cellular responses to DSBs at multiple levels, often involving extensive crosstalk between these modifications. Recent findings have revealed compelling insights into the complex mechanisms by which ubiquitin and UBLs regulate protein interactions with DSB sites to promote accurate lesion repair and protection of genome integrity in mammalian cells. These advances offer new therapeutic opportunities for diseases linked to genetic instability.

Transcription-coupled nucleotide-excision repair (TC-NER) is a subpathway of NER that efficiently removes the highly toxic RNA polymerase II blocking lesions in DNA. Defective TC-NER gives rise to the human disorders Cockayne syndrome and UV-sensitive syndrome (UV(S)S). NER initiating factors are known to be regulated by ubiquitination. Using a SILAC-based proteomic approach, we identified UVSSA (formerly known as KIAA1530) as part of a UV-induced ubiquitinated protein complex. Knockdown of UVSSA resulted in TC-NER deficiency. UVSSA was found to be the causative gene for UV(S)S, an unresolved NER deficiency disorder. The UVSSA protein interacts with elongating RNA polymerase II, localizes specifically to UV-induced lesions, resides in chromatin-associated TC-NER complexes and is implicated in stabilizing the TC-NER master organizing protein ERCC6 (also known as CSB) by delivering the deubiquitinating enzyme USP7 to TC-NER complexes. Together, these findings indicate that UVSSA-USP7–mediated stabilization of ERCC6 represents a critical regulatory mechanism of TC-NER in restoring gene expression.

The epigenetic mark indicative of DNA UV damage or double-strand breaks is achieved via a common pathway regardless of the cause of damage.

DNA ‐protein crosslinks ( DPC s) are highly cytotoxic lesions that obstruct essential DNA transactions and whose resolution is critical for cell and organismal fitness. However, the mechanisms by which cells respond to and overcome DPC s remain incompletely understood. Recent studies unveiled a dedicated DPC repair pathway in higher eukaryotes involving the SprT‐type metalloprotease SPRTN / DVC 1, which proteolytically processes DPC s during DNA replication in a ubiquitin‐regulated manner. Here, we show that chemically induced and defined enzymatic DPC s trigger potent chromatin SUMO ylation responses targeting the crosslinked proteins and associated factors. Consequently, inhibiting SUMO ylation compromises DPC clearance and cellular fitness. We demonstrate that ACRC / GCNA family SprT proteases interact with SUMO and establish important physiological roles of Caenorhabditis elegans GCNA ‐1 and SUMO ylation in promoting germ cell and embryonic survival upon DPC formation. Our findings provide first global insights into signaling responses to DPC s and reveal an evolutionarily conserved function of SUMO ylation in facilitating responses to these lesions in metazoans that may complement replication‐coupled DPC resolution processes.