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Cells From Long-Lived Mutant Mice Exhibit Enhanced Repair of Ultraviolet Lesions

¹ Cellular and Molecular Biology Graduate Program, and ² Department of Radiation Oncology, Division of Radiation & Cancer Biology, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor.
³ Department of Pathology, Geriatrics Center, and VA Medical Center, University of Michigan, Ann Arbor.

Address correspondence to Richard A. Miller, MD, PhD, Room 3001, BSRB Box 2200, 109 Zina Pitcher Place, Ann Arbor, MI 48109-0940. E-mail: millerr{at}umich.edu

Fibroblasts isolated from long-lived hypopituitary dwarf mice are resistant to many cell stresses, including ultraviolet (UV) light and methyl methane sulfonate (MMS), which induce cell death by producing DNA damage. Here we report that cells from Snell dwarf mice recover more rapidly than controls from the inhibition of RNA synthesis induced by UV damage. Recovery of messenger RNA (mRNA) synthesis in particular is more rapid in dwarf cells, suggesting enhanced repair of the actively transcribing genes in dwarf-derived cells. At early time points, there was no difference in the repair of cyclobutane pyrimidine dimers (CPD) or 6-4 photoproducts (6-4PP) in the whole genome, nor was there any significant difference in the repair of UV lesions in specific genes. However, at later time points we found that more lesions had been removed from the genome of dwarf-derived cells. We have also found that cells from dwarf mice express higher levels of the nucleotide excision repair proteins XPC and CSA, suggesting a causal link to enhanced DNA repair. Overall, these data suggest a mechanism for the UV resistance of Snell dwarf-derived fibroblasts that could contribute to the delay of aging and neoplasia in these mice.

Key Words: Longevity • Nucleotide excision repair • Snell dwarf • Stress resistance • Ultraviolet light

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