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.
Fischer
Joshua L
JL
Department of Microbiology and Walther Oncology Center, Indiana University Simon Cancer Center and Walther Cancer Institute, Indianapolis, 46202, USA.
Kumar
M A Suresh
MA
Day
Travis W
TW
Hardy
Tabitha M
TM
Hamilton
Shari
S
Besch-Williford
Cynthia
C
Safa
Ahmad R
AR
Pollok
Karen E
KE
Smith
Martin L
ML
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