Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene

The xeroderma pigmentosum group G (XP-G) gene (XPG) encodes a structure-spe cific DNA endonuclease that functions in nucleotide excision repair (NER). XP-G patients show various symptoms, ranging from mild cutaneous abnormalit ies to severe dermatological impairments. In some cases, patients exhibit g rowth failure and life-shortening and neurological dysfunctions, which are characteristics of Cockayne syndrome (CS). The known XPG protein function a s the 3' nuclease in NER, however, cannot explain the development of CS in certain XP-G patients. To gain an insight into the functions of the XPG pro tein, we have generated and examined mice lacking xpg (the mouse counterpar t of the human XPG gene) alleles. The xpg-deficient mice exhibited postnata l growth failure and underwent premature death. Since XPA-deficient mice, w hich are totally defective in NER, do not show such symptoms, our data indi cate that XPG performs an additional function(s) besides its role in NER Ou r in vitro studies showed that primary embryonic fibroblasts isolated from the xpg-deficient mice underwent premature senescence and exhibited the ear ly onset of immortalization and accumulation of p53.