Altered Replication in Human Cells Promotes DMPK (CTG)(n) · (CAG)(n) Repeat Instability

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2012 Feb 23

PMID 22354993

Citations 34

Authors

Guoqi Liu

Xiaomi Chen

Yanzhe Gao

Todd Lewis

Joanna Barthelemy

Michael Leffak

Affiliations

Soon will be listed here.

Abstract

Myotonic dystrophy type 1 (DM1) is associated with expansion of (CTG)(n) · (CAG)(n) trinucleotide repeats (TNRs) in the 3' untranslated region (UTR) of the DMPK gene. Replication origins are cis-acting elements that potentiate TNR instability; therefore, we mapped replication initiation sites and prereplication complex protein binding within the ~10-kb DMPK/SIX5 locus in non-DM1 and DM1 cells. Two origins, IS(DMPK) and IS(SIX5), flanked the (CTG)(n) · (CAG)(n) TNRs in control cells and in DM1 cells. Orc2 and Mcm4 bound near each of the replication initiation sites, but a dramatic change in (CTG)(n) · (CAG)(n) replication polarity was not correlated with TNR expansion. To test whether (CTG)(n) · (CAG)(n) TNRs are cis-acting elements of instability in human cells, model cell lines were created by integration of cassettes containing the c-myc replication origin and (CTG)(n) · (CAG)(n) TNRs in HeLa cells. Replication forks were slowed by (CTG)(n) · (CAG)(n) TNRs in a length-dependent manner independent of replication polarity, implying that expanded (CTG)(n) · (CAG)(n) TNRs lead to replication stress. Consistent with this prediction, TNR instability increased in the HeLa model cells and DM1 cells upon small interfering RNA (siRNA) knockdown of the fork stabilization protein Claspin, Timeless, or Tipin. These results suggest that aberrant DNA replication and TNR instability are linked in DM1 cells.

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References

Branzei D, Foiani M . The checkpoint response to replication stress. DNA Repair (Amst). 2009; 8(9):1038-46. DOI: 10.1016/j.dnarep.2009.04.014. View

Ritzi M, Baack M, Musahl C, Romanowski P, Laskey R, Knippers R . Human minichromosome maintenance proteins and human origin recognition complex 2 protein on chromatin. J Biol Chem. 1998; 273(38):24543-9. DOI: 10.1074/jbc.273.38.24543. View

DePamphilis M, Blow J, Ghosh S, Saha T, Noguchi K, Vassilev A . Regulating the licensing of DNA replication origins in metazoa. Curr Opin Cell Biol. 2006; 18(3):231-9. DOI: 10.1016/j.ceb.2006.04.001. View

Wu Y, Suhasini A, Brosh Jr R . Welcome the family of FANCJ-like helicases to the block of genome stability maintenance proteins. Cell Mol Life Sci. 2008; 66(7):1209-22. PMC: 2663010. DOI: 10.1007/s00018-008-8580-6. View

Xu W, Aparicio J, Aparicio O, Tavare S . Genome-wide mapping of ORC and Mcm2p binding sites on tiling arrays and identification of essential ARS consensus sequences in S. cerevisiae. BMC Genomics. 2006; 7:276. PMC: 1657020. DOI: 10.1186/1471-2164-7-276. View

Kemp M, Ghosh M, Liu G, Leffak M . The histone deacetylase inhibitor trichostatin A alters the pattern of DNA replication origin activity in human cells. Nucleic Acids Res. 2005; 33(1):325-36. PMC: 546162. DOI: 10.1093/nar/gki177. View

Lia A, Seznec H, Hofmann-Radvanyi H, Radvanyi F, Duros C, Saquet C . Somatic instability of the CTG repeat in mice transgenic for the myotonic dystrophy region is age dependent but not correlated to the relative intertissue transcription levels and proliferative capacities. Hum Mol Genet. 1998; 7(8):1285-91. DOI: 10.1093/hmg/7.8.1285. View

Voineagu I, Freudenreich C, Mirkin S . Checkpoint responses to unusual structures formed by DNA repeats. Mol Carcinog. 2009; 48(4):309-18. PMC: 2705927. DOI: 10.1002/mc.20512. View

Trinh T, Sinden R . Preferential DNA secondary structure mutagenesis in the lagging strand of replication in E. coli. Nature. 1991; 352(6335):544-7. DOI: 10.1038/352544a0. View

10.

Cimprich K, Cortez D . ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008; 9(8):616-27. PMC: 2663384. DOI: 10.1038/nrm2450. View

11.

Mirkin S . Expandable DNA repeats and human disease. Nature. 2007; 447(7147):932-40. DOI: 10.1038/nature05977. View

12.

Hashem V, Pytlos M, Klysik E, Tsuji K, Khajavi M, Khajav M . Chemotherapeutic deletion of CTG repeats in lymphoblast cells from DM1 patients. Nucleic Acids Res. 2004; 32(21):6334-46. PMC: 535684. DOI: 10.1093/nar/gkh976. View

13.

Guiraud-Dogan C, Huguet A, Gomes-Pereira M, Brisson E, Bassez G, Junien C . DM1 CTG expansions affect insulin receptor isoforms expression in various tissues of transgenic mice. Biochim Biophys Acta. 2007; 1772(11-12):1183-91. DOI: 10.1016/j.bbadis.2007.08.004. View

14.

Kemp M, Akan Z, Yilmaz S, Grillo M, Smith-Roe S, Kang T . Tipin-replication protein A interaction mediates Chk1 phosphorylation by ATR in response to genotoxic stress. J Biol Chem. 2010; 285(22):16562-71. PMC: 2878033. DOI: 10.1074/jbc.M110.110304. View

15.

Abdurashidova G, Danailov M, Ochem A, Triolo G, Djeliova V, Radulescu S . Localization of proteins bound to a replication origin of human DNA along the cell cycle. EMBO J. 2003; 22(16):4294-303. PMC: 175794. DOI: 10.1093/emboj/cdg404. View

16.

Pearson C, Edamura K, Cleary J . Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet. 2005; 6(10):729-42. DOI: 10.1038/nrg1689. View

17.

Maurer D, OCallaghan B, Livingston D . Orientation dependence of trinucleotide CAG repeat instability in Saccharomyces cerevisiae. Mol Cell Biol. 1996; 16(12):6617-22. PMC: 231663. DOI: 10.1128/MCB.16.12.6617. View

18.

Chini C, Chen J . Human claspin is required for replication checkpoint control. J Biol Chem. 2003; 278(32):30057-62. DOI: 10.1074/jbc.M301136200. View

19.

MacAlpine D, Rodriguez H, Bell S . Coordination of replication and transcription along a Drosophila chromosome. Genes Dev. 2004; 18(24):3094-105. PMC: 535919. DOI: 10.1101/gad.1246404. View

20.

Cha R, Kleckner N . ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones. Science. 2002; 297(5581):602-6. DOI: 10.1126/science.1071398. View