Functional interplay of p53 and Mus81 in DNA damage responses and cancer.
Mus81 plays an integral role in the maintenance of genome stability and DNA repair in mammalian cells. Deficiency of Mus81 in human and mouse cells results in hypersensitivity to interstrand cross-linking (ICL) agents and elevated levels of genomic instability. Furthermore, Mus81-mutant mice are susceptible to spontaneous lymphomas. The role of cellular checkpoints in mediating the phenotypes observed in Mus81-deficient cells and mice is currently unknown. In this study, we have observed increased activation of p53 in Mus81(-/-) cells in response to ICL-induced DNA damage. In addition, p53 inactivation completely rescued the ICL hypersensitivity of Mus81(-/-) cells, signifying p53 is essential for the elimination of ICL-damaged cells in the absence of Mus81. Confirming that p53 acts as a critical checkpoint for the Mus81 repair pathway, a synergistic increase of spontaneous and ICL-induced genomic instability was observed in Mus81(-/-)p53(-/-) cells. To clarify the genetic interactions of Mus81 and p53 in tumor suppression, we monitored Mus81(-/-)p53(-/-) and control mice for the development of spontaneous tumors. Significantly, we show that loss of even a single allele of Mus81 drastically modifies the tumor spectrum of p53-mutant mice and increases their predisposition to developing sarcomas. Our results reveal a key role for p53 in mediating the response to spontaneous and ICL-induced DNA damage that occurs in the absence of Mus81. Furthermore, our data show that loss of Mus81, in addition to p53, is a key step in sarcoma development.
Pamidi
Ashwin
A
The Advanced Medical Discovery Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Cardoso
Renato
R
Hakem
Anne
A
Matysiak-Zablocki
Elzbieta
E
Poonepalli
Anuradha
A
Tamblyn
Laura
L
Perez-Ordonez
Bayardo
B
Hande
M Prakash
MP
Sanchez
Otto
O
Hakem
Razqallah
R
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D048708:Cell Growth Processes / Q000235:genetics / Q000276:immunology; D004247:DNA / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D004720:Endonucleases / Q000172:deficiency / Q000235:genetics*; D005260:Female; D016195:G2 Phase / Q000502:physiology; D020868:Gene Silencing; D016158:Genes, p53; D042822:Genomic Instability; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*
D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D004247:DNA; D004720:Endonucleases; C498773:Mus81 protein, mouse