XPG: a multitasking genome caretaker

The XPG/ERCC5 endonuclease was originally identified as the causative gene for Xeroderma Pigmentosum complementation group G. Ever since its discovery, in depth biochemical, structural and cell biological studies have provided detailed mechanistic insight into its function in excising DNA damage in nucleotide excision repair, together with the ERCC1–XPF endonuclease. In recent years, it has become evident that XPG has additional important roles in genome maintenance that are independent of its function in NER, as XPG has been implicated in protecting replication forks by promoting homologous recombination as well as in resolving R-loops. Here, we provide an overview of the multitasking of XPG in genome maintenance, by describing in detail how its activity in NER is regulated and the evidence that points to important functions outside of NER. Furthermore, we present the various disease phenotypes associated with inherited XPG deficiency and discuss current ideas on how XPG deficiency leads to these different types of disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04194-5.