Murine Pif1 Interacts with Telomerase and is Dispensable for Telomere Function in Vivo

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2006 Nov 30

PMID 17130244

Citations 45

Authors

Bryan E Snow

Maria Mateyak

Jana Paderova

Andrew Wakeham

Caterina Iorio

Virginia Zakian

Jeremy Squire

Lea Harrington

Affiliations

Soon will be listed here.

Abstract

Pif1 is a 5'-to-3' DNA helicase critical to DNA replication and telomere length maintenance in the budding yeast Saccharomyces cerevisiae. ScPif1 is a negative regulator of telomeric repeat synthesis by telomerase, and recombinant ScPif1 promotes the dissociation of the telomerase RNA template from telomeric DNA in vitro. In order to dissect the role of mPif1 in mammals, we cloned and disrupted the mPif1 gene. In wild-type animals, mPif1 expression was detected only in embryonic and hematopoietic lineages. mPif1(-/-) mice were viable at expected frequencies, displayed no visible abnormalities, and showed no reproducible alteration in telomere length in two different null backgrounds, even after several generations. Spectral karyotyping of mPif1(-/-) fibroblasts and splenocytes revealed no significant change in chromosomal rearrangements. Furthermore, induction of apoptosis or DNA damage revealed no differences in cell viability compared to what was found for wild-type fibroblasts and splenocytes. Despite a novel association of mPif1 with telomerase, mPif1 did not affect the elongation activity of telomerase in vitro. Thus, in contrast to what occurs with ScPif1, murine telomere homeostasis or genetic stability does not depend on mPif1, perhaps due to fundamental differences in the regulation of telomerase and/or telomere length between mice and yeast or due to genetic redundancy with other DNA helicases.

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References

Ivessa A, Zhou J, Schulz V, Monson E, Zakian V . Saccharomyces Rrm3p, a 5' to 3' DNA helicase that promotes replication fork progression through telomeric and subtelomeric DNA. Genes Dev. 2002; 16(11):1383-96. PMC: 186315. DOI: 10.1101/gad.982902. View

Lo A, Sprung C, Fouladi B, Pedram M, Sabatier L, Ricoul M . Chromosome instability as a result of double-strand breaks near telomeres in mouse embryonic stem cells. Mol Cell Biol. 2002; 22(13):4836-50. PMC: 133890. DOI: 10.1128/MCB.22.13.4836-4850.2002. View

Zhou J, Qi H, Schulz V, Mateyak M, Monson E, Zakian V . Schizosaccharomyces pombe pfh1+ encodes an essential 5' to 3' DNA helicase that is a member of the PIF1 subfamily of DNA helicases. Mol Biol Cell. 2002; 13(6):2180-91. PMC: 117634. DOI: 10.1091/mbc.02-02-0021. View

Williams B, Lustig A . The paradoxical relationship between NHEJ and telomeric fusion. Mol Cell. 2003; 11(5):1125-6. DOI: 10.1016/s1097-2765(03)00200-4. View

Myung K, Pennaneach V, Kats E, Kolodner R . Saccharomyces cerevisiae chromatin-assembly factors that act during DNA replication function in the maintenance of genome stability. Proc Natl Acad Sci U S A. 2003; 100(11):6640-5. PMC: 164500. DOI: 10.1073/pnas.1232239100. View

Taggart A, Zakian V . Telomerase: what are the Est proteins doing?. Curr Opin Cell Biol. 2003; 15(3):275-80. DOI: 10.1016/s0955-0674(03)00040-1. View

Khakhar R, Cobb J, Bjergbaek L, Hickson I, Gasser S . RecQ helicases: multiple roles in genome maintenance. Trends Cell Biol. 2003; 13(9):493-501. DOI: 10.1016/s0962-8924(03)00171-5. View

Lydall D . Hiding at the ends of yeast chromosomes: telomeres, nucleases and checkpoint pathways. J Cell Sci. 2003; 116(Pt 20):4057-65. DOI: 10.1242/jcs.00765. View

Stellwagen A, Haimberger Z, Veatch J, Gottschling D . Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev. 2003; 17(19):2384-95. PMC: 218076. DOI: 10.1101/gad.1125903. View

10.

Bertuch A, Lundblad V . Which end: dissecting Ku's function at telomeres and double-strand breaks. Genes Dev. 2003; 17(19):2347-50. DOI: 10.1101/gad.1146603. View

11.

Ooi S, Shoemaker D, Boeke J . DNA helicase gene interaction network defined using synthetic lethality analyzed by microarray. Nat Genet. 2003; 35(3):277-86. DOI: 10.1038/ng1258. View

12.

Lustig A . Clues to catastrophic telomere loss in mammals from yeast telomere rapid deletion. Nat Rev Genet. 2003; 4(11):916-23. DOI: 10.1038/nrg1207. View

13.

Ivessa A, Lenzmeier B, Bessler J, Goudsouzian L, Schnakenberg S, Zakian V . The Saccharomyces cerevisiae helicase Rrm3p facilitates replication past nonhistone protein-DNA complexes. Mol Cell. 2003; 12(6):1525-36. DOI: 10.1016/s1097-2765(03)00456-8. View

14.

Kim N, Piatyszek M, Prowse K, Harley C, WEST M, Ho P . Specific association of human telomerase activity with immortal cells and cancer. Science. 1994; 266(5193):2011-5. DOI: 10.1126/science.7605428. View

15.

MYERS R, Stahl F . Chi and the RecBC D enzyme of Escherichia coli. Annu Rev Genet. 1994; 28:49-70. DOI: 10.1146/annurev.ge.28.120194.000405. View

16.

Torres J, Bessler J, Zakian V . Local chromatin structure at the ribosomal DNA causes replication fork pausing and genome instability in the absence of the S. cerevisiae DNA helicase Rrm3p. Genes Dev. 2004; 18(5):498-503. PMC: 374232. DOI: 10.1101/gad.1154704. View

17.

Torres J, Schnakenberg S, Zakian V . Saccharomyces cerevisiae Rrm3p DNA helicase promotes genome integrity by preventing replication fork stalling: viability of rrm3 cells requires the intra-S-phase checkpoint and fork restart activities. Mol Cell Biol. 2004; 24(8):3198-212. PMC: 381616. DOI: 10.1128/MCB.24.8.3198-3212.2004. View

18.

Ding H, Schertzer M, Wu X, Gertsenstein M, Selig S, Kammori M . Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell. 2004; 117(7):873-86. DOI: 10.1016/j.cell.2004.05.026. View

19.

Bennett R, Keck J . Structure and function of RecQ DNA helicases. Crit Rev Biochem Mol Biol. 2004; 39(2):79-97. DOI: 10.1080/10409230490460756. View

20.

Ryu G, Tanaka H, Kim D, Kim J, Bae S, Kwon Y . Genetic and biochemical analyses of Pfh1 DNA helicase function in fission yeast. Nucleic Acids Res. 2004; 32(14):4205-16. PMC: 514361. DOI: 10.1093/nar/gkh720. View