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Pif1 key element in repairing broken DNA

A break of the chromosome can spell trouble for a cell.

However, cells have mechanisms for repair that require the copying of DNA from intact template chromosome to mend the breach.

In a report that appeared in the journal Nature, a consortium of researchers including those at Baylor College of Medicine describe an enzyme called Pif1 that promotes the extensive DNA synthesis that occurs through a specific mechanism called D-loop migration.

"This is a fundamental discovery because it demonstrates that extensive DNA synthesis during the repair of chromosomal breaks can occur via a mechanism completely different from the one used in regular chromosomes replication. Instead of the helicase used for replication of chromosomes called Mcm2-7, we found that the Pif1 helicase is very important for the extensive repair-specific DNA synthesis," said Dr. Gregory Ira, associate professor of molecular and human genetics at BCM and senior author of the report. (A DNA helicase acts like the pull on a zipper, separating the two strands of DNA during replication. The separation allows each DNA strand to be copied.)

Repair of DNA breaks

Pif1 also changes the way in which DNA is synthesized. When DNA is replicated, a structure called the replication fork is formed after helicases break the hydrogen bonds that hold the two DNA strands together. Each prong of the fork is a single strand of DNA. Special enzymes called DNA polymerases then use these single strands as templates for making complementary strand of a DNA. Therefore upon replication, each DNA molecule contains one of the original strands and one new strand. Pif1, however uses a process called D-loop migration, in which the newly synthesized strand is immediately unwound from its template and itself serves as a template for the production of the complementary strand. That means that new strands are inherited by a single DNA molecule and that the proteins that are designed to repair polymerase errors have a shortened time in which to do so.

"This mechanism is very important for the repair of DNA breaks that require extensive DNA synthesis, and in certain type of cancers, it is essential to maintain chromosome ends called telomeres," said Ira.

Collaborators

Ira credits his collaborators with contributing to this research, including Drs. Patrick Sung and Youngho Kwon of Yale University School of Medicine who performed the biochemical experiments and Dr. Anna Malkova then of Indiana University - Purdue University in Indianapolis, with whom he has collaborated for years on the mechanisms of break-induced replication.

Others who took part in this work include: Marenda A. Wilson; Woo-Hyun Chung; Ryan Mayle and Xuefeng Chen, all of BCM; Yuanyuan Xu;Peter Chi and Hengyao Niu, both of Yale. Chung is now with the College of Pharmacy at Duksung Women’s University in Seoul, South Korea.

Chi is also with the Institute of Biochemical Sciences at National Taiwan University and the Institute of Biological Chemistry, Academia Sinica, both in Taipei.

Funding for this work came from the United States National Institutes of Health (GM080600, ES007061, GM057814, ES015632, GM084242, T32 GM07526-34): National Research Foundation of Korea: cademia Sinica National Taiwan University and the National Science Council of Taiwan.