Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 3397-3406 |
| Number of pages | 10 |
| Journal | Human molecular genetics |
| Volume | 18 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - 04-09-2009 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Genetics(clinical)
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Impaired DNA replication prompts deletions within palindromic sequences, but does not induce translocations in human cells. / Kurahashi, Hiroki; Inagaki, Hidehito; Kato, Takema; Hosoba, Eriko; Kogo, Hiroshi; Ohye, Tamae; Tsutsumi, Makiko; Bolor, Hasbaira; Tong, Maoqing; Emanuel, Beverly S.
In: Human molecular genetics, Vol. 18, No. 18, 04.09.2009, p. 3397-3406.Research output: Contribution to journal › Article
TY - JOUR
T1 - Impaired DNA replication prompts deletions within palindromic sequences, but does not induce translocations in human cells
AU - Kurahashi, Hiroki
AU - Inagaki, Hidehito
AU - Kato, Takema
AU - Hosoba, Eriko
AU - Kogo, Hiroshi
AU - Ohye, Tamae
AU - Tsutsumi, Makiko
AU - Bolor, Hasbaira
AU - Tong, Maoqing
AU - Emanuel, Beverly S.
PY - 2009/9/4
Y1 - 2009/9/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=69449106659&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=69449106659&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddp279
DO - 10.1093/hmg/ddp279
M3 - Article
C2 - 19520744
AN - SCOPUS:69449106659
VL - 18
SP - 3397
EP - 3406
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 18
ER -