Top1 May Do More Than Relax DNA

The diagram presents a possible model for Top1-initiated deletions. The top strand is the non-transcribed DNA strand.  At an A-T-A-T dinucleotide repeat hotspot in the lower strand (highlighted in gray), a ribo-uracil replaces a thymidine base at Top1 cleavage site.  The cyclic 2′,3′-phosphate formed by Top1 cleavage is marked with a red triangle.

The diagram presents a possible model for Top1-initiated deletions. The top strand is the non-transcribed DNA strand. At an A-T-A-T dinucleotide repeat hotspot in the lower strand (highlighted in gray), a ribo-uracil replaces a thymidine base at Top1 cleavage site. The cyclic 2′,3′-phosphate formed by Top1 cleavage is marked with a red triangle.

Topoisomerase 1 (Top1) is an enzyme with a well known role in relaxing DNA supercoils by making reversible nicks in DNA. The ribonuclease (RNase) H class of enzymes is equally well known for removing ribonucleotides from hybrid duplex DNA when they are misincorporated during DNA replication. Recently, Shar-yin Huang, Ph.D., and Yves Pommier, M.D., Ph.D., in CCR’s Laboratory of Molecular Pharmacology teamed up with Sue Jinks-Robertson of Duke University’s Department of Molecular Genetics and Microbiology and Thomas Kunkel of the NIEHS, NIH to show that in yeast, Top1 can act like the RNase H class enzymes and convert misincorporated single ribonucleotides into irreversible single-strand breaks, an activity that produces deletion mutations.  They reported this discovery in Science.

The researchers used the ability of the anticancer drug camptothecin to stabilize the DNA nicks created by Top1 and found that in certain genomic regions rich in short tandem repeats, if a ribo-uracil is substituted for a normal DNA base, the yeast Top1 cleaves the site irreversibly, eventually giving rise to deletion mutations.  This Top1 activity occurred in conjunction with transcription, not replication, so the deletion errors were not corrected by the yeast’s mismatch repair system. 

This discovery of a new role for Top1 in yeast may have relevance to cancer because this (RNase) H class-like activity of Top1 could possibly have a counterpart activity in terminally differentiated cells where it also might produce deletion mutations.   This new role for Top1 might even contribute to  the microsatellite instability often seen in tumors over-expressing Top1.

Summary Posted: 06/2011

Reference

Reviewed by Donna Kerrigan PubMed Link