Slowdown in DNA Replication Leads to Cancer-Forming Genomic Damage

In a recent publication, cancer researchers described a mechanism for the formation of breakage in DNA at specific “fragile sites” that induced chromosomal instability, which is characteristic of cells in the early stages of cancer development.

Investigators at the Hebrew University of Jerusalem (Israel) employed sophisticated new methodology that allowed the study of single DNA molecules to study the basis for the formation of breaks at specific fragile sites.

They reported in the July 8, 2011, issue of the journal Molecular Cell that even under normal growth conditions, replication fork progression along the fragile chromosome site, FRA16C, was slow, and forks frequently stalled at adenine-thymine (A-T) rich sequences, leading to activation of additional origins to enable replication completion. Under mild replication stress, the frequency of stalling at A-T-rich sequences was further increased. Unlike in the entire genome, in the FRA16C region additional origins were not activated, suggesting that all potential origins were already activated under normal conditions.

The basis for FRA16C fragility was replication fork stalling at A-T-rich sequences and the inability of the cell to activate additional origins under replication stress. These results provide a mechanism explaining the replication stress sensitivity of fragile sites and thus, the basis for genomic instability during early stages of cancer development.

“A hallmark of most human cancers is accumulation of damage in the DNA, which drives cancer development,” said senior author Dr. Batsheva Kerem, professor of genetics at the Hebrew University of Jerusalem. “In the early stages of cancer development, the cells are forced to proliferate. In each cycle of proliferation, the DNA is replicated to ensure that the daughter cells have a full DNA. However, in these early stages the conditions for DNA replication are perturbed, leading to DNA breaks, which occur specifically in regions defined as ‘fragile sites.’”

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Hebrew University of Jerusalem