The DNA replication machinery encounters problems at numerous genomic regions that are inherently difficult to replicate. These genomic regions include telomeres, which contain repetitive DNA and telomere-binding proteins. If not properly regulated, replication of such genomic regions can result in DNA damage, leading to genomic instability. Studies implicated a role of Timeless-related proteins at difficult-to-replicate genomic regions, including telomeres. However, how these proteins maintain telomeres was elusive. In a recent report, we described the role of Swi1, a Timeless-related protein, in telomere maintenance in fission yeast. We demonstrated that Swi1 is required for proper replication of repeat DNA sequences at telomeres. We also showed that Swi1-deficient cells utilize recombination-based ALT (alternative lengthening of telomeres)-like mechanisms to maintain telomeres in the absence of telomerase. Here, we highlight these findings and present additional data to discuss the role of Swi1Timeless in telomere protection and ALT prevention.
KeywordsSwi1 Timeless FPC Fork protection complex Telomeres Myb/SANT Tbf1 ALT Alternative lengthening of telomeres Replication fork Genomic integrity Repeat DNA Cancer
This work was supported by the Aging Initiative at Drexel University College of Medicine. We thank Chiaki Noguchi and Grant Grothusen for technical assistance and National BioResource Project Japan for S. pombe strains.
- Cherng N, Shishkin AA, Schlager LI, Tuck RH, Sloan L, Matera R, Sarkar PS, Ashizawa T, Freudenreich CH, Mirkin SM (2011) Expansions, contractions, and fragility of the spinocerebellar ataxia type 10 pentanucleotide repeat in yeast. Proc Natl Acad Sci USA 108:2843–2848. doi: 10.1073/pnas.1009409108 CrossRefPubMedPubMedCentralGoogle Scholar
- Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suva ML, Benes CH, Haber DA, Boussin FD, Zou L (2015) Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347:273–277. doi: 10.1126/science.1257216 CrossRefPubMedPubMedCentralGoogle Scholar
- Rapp JB, Noguchi C, Das MM, Wong LK, Ansbach AB, Holmes AM, Arcangioli B, Noguchi E (2010) Checkpoint-dependent and -independent roles of Swi3 in replication fork recovery and sister chromatid cohesion in fission yeast. PLoS One 5:e13379. doi: 10.1371/journal.pone.0013379 CrossRefPubMedPubMedCentralGoogle Scholar
- Rozenzhak S, Mejia-Ramirez E, Williams JS, Schaffer L, Hammond JA, Head SR, Russell P (2010) Rad3 decorates critical chromosomal domains with gammaH2A to protect genome integrity during S-Phase in fission yeast. PLoS Genet 6:e1001032. doi: 10.1371/journal.pgen.1001032 CrossRefPubMedPubMedCentralGoogle Scholar
- Sabouri N, McDonald KR, Webb CJ, Cristea IM, Zakian VA (2012) DNA replication through hard-to-replicate sites, including both highly transcribed RNA Pol II and Pol III genes, requires the S. pombe Pfh1 helicase. Genes Dev 26:581–593. doi: 10.1101/gad.184697.111 CrossRefPubMedPubMedCentralGoogle Scholar
- Sommariva E, Pellny TK, Karahan N, Kumar S, Huberman JA, Dalgaard JZ (2005) Schizosaccharomyces pombe Swi1, Swi3, and Hsk1 are components of a novel S-phase response pathway to alkylation damage. Mol Cell Biol 25:2770–2784. doi: 10.1128/MCB.25.7.2770-2784.2005 CrossRefPubMedPubMedCentralGoogle Scholar