Journal Article

Impaired DNA replication prompts deletions within palindromic sequences, but does not induce translocations in human cells

Hiroki Kurahashi, Hidehito Inagaki, Takema Kato, Eriko Hosoba, Hiroshi Kogo, Tamae Ohye, Makiko Tsutsumi, Hasbaira Bolor, Maoqing Tong and Beverly S. Emanuel

in Human Molecular Genetics

Volume 18, issue 18, pages 3397-3406
Published in print September 2009 | ISSN: 0964-6906
Published online June 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp279
Impaired DNA replication prompts deletions within palindromic sequences, but does not induce translocations in human cells

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Palindromic regions are unstable and susceptible to deletion in prokaryotes and eukaryotes possibly due to stalled or slow replication. In the human genome, they also appear to become partially or completely deleted, while two palindromic AT-rich repeats (PATRR) contribute to known recurrent constitutional translocations. To explore the mechanism that causes the development of palindrome instabilities in humans, we compared the incidence of de novo translocations and deletions at PATRRs in human cells. Using a highly sensitive PCR assay that can detect single molecules, de novo deletions were detected neither in human somatic cells nor in sperm. However, deletions were detected at low frequency in cultured cell lines. Inhibition of DNA replication by administration of siRNA against the DNA polymerase alpha 1 (POLA1) gene or introduction of POLA inhibitors increased the frequency. This is in contrast to PATRR-mediated translocations that were never detected in similar conditions but were observed frequently in human sperm samples. Further deletions were found to take place during both leading- and lagging-strand synthesis. Our data suggest that stalled or slow replication induces deletions within PATRRs, but that other mechanisms might contribute to PATRR-mediated recurrent translocations in humans.

Journal Article.  5847 words.  Illustrated.

Subjects: Genetics and Genomics

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