Spi-1/PU.1 oncogene accelerates DNA replication fork elongation and promotes genetic instability in the absence of DNA breakage.
The multistage process of cancer formation is driven by the progressive acquisition of somatic mutations. Replication stress creates genomic instability in mammals. Using a well-defined multistep leukemia model driven by Spi-1/PU.1 overexpression in the mouse and Spi-1/PU.1-overexpressing human leukemic cells, we investigated the relationship between DNA replication and cancer progression. Here, using DNA molecular combing and flow cytometry methods, we show that Spi-1 increases the speed of replication by acting specifically on elongation rather than enhancing origin firing. This shortens the S-phase duration. Combining data from Spi-1 knockdown in murine cells with Spi-1 overexpression in human cells, we provide evidence that inappropriate Spi-1 expression is directly responsible for the replication alteration observed. Importantly, the acceleration of replication progression coincides with an increase in the frequency of genomic mutations without inducing DNA breakage. Thus, we propose that the hitherto unsuspected role for spi-1 oncogene in promoting replication elongation and genomic mutation promotes blastic progression during leukemic development.
Rimmelé
Pauline
P
Institut Curie, INSERM U830, Paris, France.
Komatsu
Jun
J
Hupé
Philippe
P
Roulin
Christophe
C
Barillot
Emmanuel
E
Dutreix
Marie
M
Conseiller
Emmanuel
E
Bensimon
Aaron
A
Moreau-Gachelin
Françoise
F
Guillouf
Christel
C
D000818:Animals; D001752:Blast Crisis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D053960:DNA Breaks; D004261:DNA Replication / Q000235:genetics*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D004900:Erythroblasts / Q000473:pathology / Q000502:physiology; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011289:Preleukemia / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D016196:S Phase / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1