The Xpc gene markedly affects cell survival in mouse bone marrow.
The XPC protein (encoded by the xeroderma pigmentosum Xpc gene) is a key DNA damage recognition factor that is required for global genomic nucleotide excision repair (G-NER). In contrast to transcription-coupled nucleotide excision repair (TC-NER), XPC and G-NER have been reported to contribute only modestly to cell survival after DNA damage. Previous studies were conducted using fibroblasts of human or mouse origin. Since the advent of Xpc-/- mice, no study has focused on the bone marrow of these mice. We used carboplatin to induce DNA damage in Xpc-/- and strain-matched wild-type mice. Using several independent methods, Xpc-/- bone marrow was approximately 10-fold more sensitive to carboplatin than the wild type. Importantly, 12/20 Xpc-/- mice died while 0/20 wild-type mice died. We conclude that G-NER, and XPC specifically, can contribute substantially to cell survival. The data are important in the context of cancer chemotherapy, where Xpc gene status and G-NER may be determinants of response to DNA-damaging agents including carboplatin. Additionally, altered cell cycles and altered DNA damage signalling may contribute to the cell survival end point.
Department of Microbiology and Walther Oncology Center, Indiana University Simon Cancer Center and Walther Cancer Institute, Indianapolis, 46202, USA.
Joshua L
JL
Fischer
M A Suresh
MA
Kumar
Travis W
TW
Day
Tabitha M
TM
Hardy
Shari
S
Hamilton
Cynthia
C
Besch-Williford
Ahmad R
AR
Safa
Karen E
KE
Pollok
Martin L
ML
Smith
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology*; D016190:Carboplatin / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002470:Cell Survival; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C501002:Xpc protein, mouse; D016190:Carboplatin