An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria

Abstract

Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the combined disorder XPCS with a G602D-encoding mutation in the Xpd helicase gene. XPCS mice are the most skin cancer-prone NER model to date, and we postulate an unusual NER dysfunction that is likely responsible for this susceptibility. XPCS mice also displayed symptoms of segmental progeria, including cachexia and progressive loss of germinal epithelium. Like CS fibroblasts, XPCS and TTD fibroblasts from human and mouse showed evidence of defective repair of oxidative DNA lesions that may underlie these segmental progeroid symptoms.

Nucleotide Excision Repair Disorders and the Balance Between Cancer and Aging

“…[10][11][12] Recently we found that both human and mouse CS and TTD cells (and also cells from the rare combined disorder, XPCS) share a common defect in repair of oxidative lesions which might explain the overlapping progeroid features of these syndromes. 13 The idea that progeria in CS, TTD and XPCS is linked to accumulated endogenous DNA damage is further supported by genetic evidence: CS, TTD and XPCS mice additionally lacking a functional Xpa gene, which further reduces NER capacity, share common dramatic phenotypes including rapid postnatal onset of progeroid features and death around weaning. [13][14][15] We note that a number of other defects in CS and/or TTD cells and mice have been reported, namely defective transcriptional activation of nuclear hormone receptors (including regulators of fat metabolism) by the TFIIH complex.…”

“…13 The idea that progeria in CS, TTD and XPCS is linked to accumulated endogenous DNA damage is further supported by genetic evidence: CS, TTD and XPCS mice additionally lacking a functional Xpa gene, which further reduces NER capacity, share common dramatic phenotypes including rapid postnatal onset of progeroid features and death around weaning. [13][14][15] We note that a number of other defects in CS and/or TTD cells and mice have been reported, namely defective transcriptional activation of nuclear hormone receptors (including regulators of fat metabolism) by the TFIIH complex. 16 However, the presence of these defects in different complementation groups of the same disease, or in both CS as well as TTD, and thus their ability to explain common disease symptoms, remains to be determined.…”

“…If gatekeeper activation due to caretaker deficiency, either on f gatekeeper activation due to caretaker deficiency, either on a cellular or organismal level, protects from cancer at the expense of accelerated aging in CS and TTD 17,30 why are XPCS patients and mice 13 with a similar CS-like defect not protected from cancer as well? Several lines of evidence show that at least in XPD-XPCS (XPD G602D ) cells, the CS type of defect is accompanied by a unique NER dysfunction-namely, in XPD-XPCS cells (but not in e.g., XPD-TTD [XPD R722W ] cells) the NER machinery "gains" a function leading to even more genome instability than failure to repair would impart on its own.…”

“…Specifically, UV damage induces incisions in the genome in the vicinity of damage without actually committing to repair, likely leading to increased genomic instability. 13,31,32 Thus in the XPCS genome, damage may accumulate more quickly than in TTD or CS, and in spite of elevated gatekeeper activation lead to cancer formation. However, if the problem of cancer formation in XPD-XPCS is increased genomic instability due to an increase in DNA breaks, this is unlikely to explain the cancer predisposition in XPCS cases associated with mutations in XPG and XPG genes.…”

“…What makes these NER disorders so unusual, and potentially informative about the connection between cancer and aging, is the coexistence of cancer and progeria in XPCS and XPTTD despite the conspicuous absence of cancer in CS and TTD. The recent findings that in XPD-TTD (XPD R722W ) animals aging is enhanced while spontaneous cancer formation reduced 30 while in XPD-XPCS (XPD G602D ) animals both processes are enhanced 13 demonstrates that cancer and aging can be experimentally modulated by a single amino acid change in one caretaker gene.…”