A new approach unveils how human cells kick off DNA replication
As cells divide, their genomic DNA is copied with precision, exactly once in every cell cycle. When this replication process goes awry, it can alter genomic DNA and promote cellular ageing, cancer, and various genetic disorders. Because of that, deciphering how cells begin duplicating their DNA is essential for understanding foundational biology, disease mechanisms, and even evolution.
Historically, DNA replication has been explored primarily in microbes like E. coli and in yeast. In these organisms, the origin of replication—the starting point of DNA duplication—is directed by a specific DNA sequence. In contrast, most eukaryotic cells, including human cells, do not rely on a fixed DNA sequence to determine replication start sites. For many years, the question of where and how replication initiates within the human genome remained unresolved.
To tackle this, Masato Kanemaki and colleagues at the National Institute of Genetics introduced a high-precision technique, LD-OK-seq (Ligase Depletion-Okazaki sequencing), to map replication initiation sites across the human genome. By examining the proteins associated with these regions, they uncovered a core principle governing how replication start sites are chosen in human cells.
Their results show that, apart from regions actively transcribed into RNA, human cells can initiate DNA replication at nearly any location across the genome. This broad initiation capability stems from widespread occupancy by the MCM helicase, a key driver of DNA replication. Moreover, the team found that early in S phase, initiation events frequently occur in intergenic regions (stretches between genes), and these sites are determined by the binding of the TRESLIN-MTBP complex, which activates the MCM helicase. They also identified an opposing regulatory mechanism that modulates how TRESLIN-MTBP binds to MCM.
Collectively, these findings answer a fundamental question about how human cells start DNA replication, offering new perspectives on diseases stemming from replication errors—such as genomic instability disorders, cancer, ageing, and other genetic conditions—and on the evolution of genomes. In the long run, this work could pave the way for technologies that deliberately control DNA replication.
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