Distinct Mechanisms of Nuclease-Directed DNA-Structure-Induced Genetic Instability in Cancer Genomes.

Abstract

Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease. Further, we found that these nucleases cleaved H-DNA conformations, and the interactions of modeled H-DNA with ERCC1-XPF, XPG, and FEN1 proteins were explored at the sub-molecular level. The results suggest mechanisms of genetic instability triggered by H-DNA through distinct structure-specific, cleavage-based replication-independent and replication-dependent pathways, providing critical evidence for a role of the DNA structure itself in the etiology of cancer and other human diseases.

• Authors: Junhua Zhao, Guliang Wang, Imee M Del Mundo, Jennifer A McKinney, Xiuli Lu, Albino Bacolla, Stephen B Boulware, Changsheng Zhang, Haihua Zhang, Pengyu Ren, Catherine H Freudenreich, Karen M Vasquez
• Journal: Cell reports (Cell Rep) Vol. 22 Issue 5 Pg. 1200-1210 (01 30 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 29386108 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA

Topics

• Chromosome Breakpoints
• DNA (chemistry, genetics)
• DNA Replication (genetics)
• DNA Sequence, Unstable (genetics)
• Genomic Instability (genetics)
• Humans
• Mutation
• Neoplasms (genetics)