Researchers Reveal New DNA Replication Pathway

ON2018-06-15TAG: ShanghaiTech UniversityCATEGORY: School of Life Science and Technology

A recent international research collaboration has shed new light on DNA replication. The collaboration, led by Professor Bo Sun from the School of Life Science and Technology at ShanghaiTech University and Professor Michelle D. Wang from the Howard Hughes Medical Institute (HHMI) and Cornell University, revealed a new replication recovery pathway. Their paper, “Helicase Promotes Replication Re-initiation from an RNA transcript,” was published online in Nature Communications on June 13th, 2018.

The DNA replication fork frequently encounters a variety of natural obstacles, such as DNA damage, stable DNA secondary structures, and DNA-bound complexes. In addition, as transcription and replication occur on the same DNA molecule simultaneously, it is inevitable that the replisome collides with the transcription complex. Such barriers, if not resolved in a timely manner, have been shown to pose threats to the progression of DNA replication forks, leading to genome instability, chromosomal rearrangements and even cancer. Several pathways, such as fork reversal, lesion skipping and translesion synthesis, have been reported to illustrate how a replication fork can be restarted when encountering an obstacle. The existence of these multiple pathways highlights the importance of replication fork recovery.

Professor Sun and Professor Wang’s research revealed a new replication recovery pathway through which the replisome is able to overcome a DNA lesion and stalled RNA polymerase (RNAP) simultaneously. Previously, they reported a direct lesion bypass pathway which only helps less than 30% of the replisome to overcome a DNA lesion (Sun et al., Nature Communications, 2015). In their latest research, they continued to use a single-molecule optical trapping technique to investigate other replication re-initiation pathways of the bacteriophage T7 replisome. They found that a non-replicating T7 DNA polymerase (DNAP) interacts strongly with a T7 helicase at a fork, and this interaction significantly reduces the helicase slippage frequency, leading to a faster and more processive unwinding. Furthermore, the T7 helicase in association with the non-replicating DNAP is able to displace an RNAP and, subsequently, the DNAP can re-initiate DNA synthesis, using the RNA transcript. These findings reveal a novel pathway of replication re-initiation enabled by the participation of a replicative helicase.

Their research was supported by grants from the National Key Research and Development Program of China, the Shanghai Pujiang Program, and ShanghaiTech University.

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Helicase assists a non-replicating DNAP in bypassing a lesion and displacing a stalled RNAP, in order to re-initiate DNA replication.