Impaired spermatogenesis and elevated spontaneous tumorigenesis in xeroderma pigmentosum group A gene (Xpa)-deficient mice

Abstract

We have reported that xeroderma pigmentosum group A (Xpa) gene-knockout mice [Xpa (−/−) mice] are deficient in nucleotide excision repair (NER) and highly sensitive to UV-induced skin carcinogenesis. Although xeroderma pigmentosum group A patients show growth retardation, immature sexual development, and neurological abnormalities as well as a high incidence of UV-induced skin tumors, Xpa (−/−) mice were physiologically and behaviorally normal. In the present study, we kept Xpa (−/−) mice for two years under specific pathogen-free (SPF) conditions and found that the testis diminished in an age-dependent manner, and degenerating seminiferous tubules and no spermatozoa were detected in the 24-month old Xpa (−/−) mice. In addition, a higher incidence of spontaneous tumorigenesis was observed in the 24-month old Xpa (−/−) mice compared to Xpa (+/+) controls. Xpa (−/−) mice provide a useful model for investigating the aging and internal tumor formation in XP-A patients.

Dual role for mammalian DNA polymerase ζ in maintaining genome stability and proliferative responses

“…These mice acquire Zymbal's and preputial gland tumors after 400-440 d (31). In contrast, 35% of NER-defective xeroderma pigmentosum group A (Xpa −/− ) mice (compared with 19% of Xpa +/+ control mice) form spontaneous tumors after 2 y, but none of these neoplasias arise in specialized sebaceous glands (32). Mice lacking the exonuclease activity of either DNA polymerase δ or e have distinct mutator and cancer phenotypes, but neither group has an increased incidence of sebaceous gland tumors (33).…”

Cockayne syndrome pathogenesis: Lessons from mouse models

“…TC-NER GG-NER >2 years 4-5 weeks No changes reported Shiomi et al (2004Shiomi et al ( , 2005 XP Xpa -/ TC-NER GG-NER >2 years -UV-hypersensitive skin and eyes, skin cancer predisposition, increased mutation frequencies; no or very mild nervous system changes Melis et al (2008) and Nakane et al (2008) Xpc À/À GG-NER >2 years Unaltered UV-hypersensitive skin and eyes, skin cancer predisposition, increased mutation frequencies; no or very mild nervous system changes Melis et al (2008) Xpg D811A/D811A Partial TC-NER partial GG-NER…”

“…Of note, single mutant Xpc À/À , Xpa À/À , as well as double mutant Xpc À/À /Xpa À/À mice develop a mild phenotype characterized by normal or near-normal life span, a mild increased risk for developing tumors, and a strongly increased propensity to develop UV-induced skin cancer (Table 1) (Melis et al, 2008;Nakane et al, 2008;van der Pluijm et al, 2007). At embryonic day 18.5 double mutant Csb m/m /Xpc À/À and Csb m/m /Xpa À/À fetuses were present at Mendelian frequencies, and were morphologically and histologically indistinguishable from wild type and single mutant fetuses, indicative for unaltered embryonic development (Laposa et al, 2007;Murai et al, 2001;van der Pluijm et al, 2007).…”

SirT1 is required in the male germ cell for differentiation and fecundity in mice

“…Consistent with this idea, we observed a reduction in SirT1 levels in the testes of aging male mice. Deletion of TAp73 (Inoue et al, 2014), GATA4 (Kyronlahti et al, 2011) and XPA (Nakane et al, 2008) results in an agedependent deterioration of seminiferous tubules, primarily due to defects in germ cell proliferation (TAp73), Sertoli cell and Leydig cell maturation and dysfunction (TAp73 and GATA4) and a lack of post-meiotic cells (TAp73, GATA4 and Xpa). Deletion of SirT1 results in accelerated reproductive aging without a loss of postmeiotic cells or defects in somatic cell abundance or function, indicating that SirT1 plays a unique role in the aging of the testes.…”