A distinct first replication cycle of DNA introduced in mammalian cells.
Many mutation events in microsatellite DNA sequences were traced to the first embryonic divisions. It was not known what makes the first replication cycles of embryonic DNA different from subsequent replication cycles. Here we demonstrate that an unusual replication mode is involved in the first cycle of replication of DNA introduced in mammalian cells. This alternative replication starts at random positions, and occurs before the chromatin is fully assembled. It is detected in various cell lines and primary cells. The presence of single-stranded regions increases the efficiency of this alternative replication mode. The alternative replication cannot progress through the A/T-rich FRA16B fragile site, while the regular replication mode is not affected by it. A/T-rich microsatellites are associated with the majority of chromosomal breakpoints in cancer. We suggest that the alternative replication mode may be initiated at the regions with immature chromatin structure in embryonic and cancer cells resulting in increased genomic instability. This work demonstrates, for the first time, differences in the replication progression during the first and subsequent replication cycles in mammalian cells.
Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA 16801, USA.
Gurangad S
GS
Chandok
Kalvin K
KK
Kapoor
Rachel M
RM
Brick
Julia M
JM
Sidorova
Maria M
MM
Krasilnikova
D020856:AT Rich Sequence; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D043283:Chromosome Fragile Sites; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D019175:DNA Methylation; D004261:DNA Replication; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018895:Microsatellite Repeats; D009707:Nucleosomes / Q000737:chemistry; D011995:Recombination, Genetic; D018741:Replication Origin; D016196:S Phase / Q000235:genetics; D013539:Simian virus 40 / Q000235:genetics; D014162:Transfection
D000952:Antigens, Polyomavirus Transforming; D009707:Nucleosomes; D004247:DNA