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. 2017 Jan 27;8(2):54.
doi: 10.3390/genes8020054.

Non-Canonical Replication Initiation: You're Fired!

Free PMC article

Non-Canonical Replication Initiation: You're Fired!

Bazilė Ravoitytė et al. Genes (Basel). .
Free PMC article


The division of prokaryotic and eukaryotic cells produces two cells that inherit a perfect copy of the genetic material originally derived from the mother cell. The initiation of canonical DNA replication must be coordinated to the cell cycle to ensure the accuracy of genome duplication. Controlled replication initiation depends on a complex interplay of cis-acting DNA sequences, the so-called origins of replication (ori), with trans-acting factors involved in the onset of DNA synthesis. The interplay of cis-acting elements and trans-acting factors ensures that cells initiate replication at sequence-specific sites only once, and in a timely order, to avoid chromosomal endoreplication. However, chromosome breakage and excessive RNA:DNA hybrid formation can cause breakinduced (BIR) or transcription-initiated replication (TIR), respectively. These non-canonical replication events are expected to affect eukaryotic genome function and maintenance, and could be important for genome evolution and disease development. In this review, we describe the difference between canonical and non-canonical DNA replication, and focus on mechanistic differences and common features between BIR and TIR. Finally, we discuss open issues on the factors and molecular mechanisms involved in TIR.

Keywords: RNA:DNA hybrid; replication control; transcription‐initiated replication.

Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.


Figure 1
Figure 1
Schematic outline of origin-dependent initiation of chromosomal and mitochondrial DNA replication. cis-acting origin DNA sequences (dotted lines), RNA (green), newly synthesized DNA (red), and helicases (green circle) are indicated. Note that chromosomal origin unwinding is driven by protein–DNA interactions, while transcription-dependent R-loop formation is a key step in mitochondrial origin-unwinding. See text for more details.
Figure 2
Figure 2
Schematic representation of possible mechanism involved in origin-independent replication initiation by inducible stable DNA replication/break-induced replication (iSDR/BIR) or constitutive stable DNA replication/transcription-initiated replication (cSDR/TIR). Invading and newly synthesized DNA (red), RNA (green), and helicases (green circle) are indicated. Dashed arrows indicate putative scenarios for TIR-dependent replication initiation. Note that none of these scenarios have been experimentally verified. See text for more details. DSB: double-strand break.

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