Z-DNA-forming sequences generate large-scale deletions in mammalian cells

Area of Science:

• Genetics
• Molecular Biology
• Genomic Instability

Background:

• Spontaneous chromosomal breakages at genomic hotspots can lead to human diseases.
• Chromosomal breakpoints in human tumors are often located near Z-DNA-forming sequences.
• The role of Z-DNA in generating chromosomal breakages remains unclear.

Purpose of the Study:

• To investigate whether Z-DNA-forming sequences induce genetic instability and chromosomal breakages.
• To compare the effects of Z-DNA in bacterial and mammalian cells.
• To elucidate the mechanisms underlying Z-DNA-induced mutations.

Main Methods:

• Introduction of Z-DNA-forming sequences into bacterial (Escherichia coli) and mammalian cells.
• Analysis of mutations, including deletions and double-strand breaks, in both cell types.
• Investigation of replication-dependent and independent mechanisms of mutation generation.

Main Results:

• Z-DNA-forming sequences induce significant genetic instability in both bacterial and mammalian cells.
• Mammalian cells exhibit Z-DNA-induced double-strand breaks and large-scale deletions (95% of mutants), dispersed over a 400-bp region.
• Bacterial cells show predominantly small deletions within repeats, with increased frequency under replication.
• Large-scale deletions in mammalian cells are partly replication-independent, suggesting initiation by repair processing.

Conclusions:

• Z-DNA-forming sequences are potent inducers of genetic instability and chromosomal breakage in mammalian cells.
• Mammalian cells process Z-DNA differently than bacteria, involving replication-independent mechanisms.
• Z-DNA may be a causative factor in gene translocations associated with leukemias and lymphomas.
• Cellular conditions like active transcription may elevate the risk of Z-DNA-related genetic instability.