High-resolution maps of DNA damage and repair

High-resolution maps of DNA damage and repair


The chemotherapy drug cisplatin destroys tumors by binding to cancer cell DNA and disrupting replication. However, some cancers develop a type of resistance through mechanisms that include the excision of damaged single-stranded oligomers from the genome and polymerization of new DNA to fill the gaps.

To help investigate this mechanism, researchers present “Damage-seq” and “XR-seq,” methods that yield single-nucleotide resolution maps of cisplatin damage and repair for the human genome.

Damage-seq identifies the precise location of DNA damage by exploiting the replication-blocking properties of base lesions. XR-seq reveals the removal of these lesions by capturing and sequencing the excised oligomer by-products that are released during DNA repair.

Using the techniques, the authors demonstrate that cisplatin-induced DNA damage is uniformly distributed in the human genome with a frequency that comports with previously published low-resolution mapping studies, whereas the rate of repair is highly heterogeneous, influenced by functional and epigenetic factors.

The findings demonstrate that Damage-seq and XR-seq can be combined to study cancer sensitivity and resistance to current drugs and potentially to develop new clinical treatment strategies, according to the authors.

http://www.pnas.org/content/113/41/11507

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