Alternative lengthening of telomeres (ALT)

Nature. 2010 Apr 8;464(7290):858-63. Epub 2010 Mar 24.
Zscan4 regulates telomere elongation and genomic stability in ES cells.
Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M, Lee SL, Stagg CA, Hoang HG, Yang HT, Indig FE, Wersto RP, Ko MS.

Developmental Genomics and Aging Section, Laboratory of Genetics, NIH, Baltimore, Maryland 21224, USA
Abstract
Exceptional genomic stability is one of the hallmarks of mouse embryonic stem (ES) cells. However, the genes contributing to this stability remain obscure. We previously identified Zscan4 as a specific marker for two-cell embryo and ES cells. Here we show that Zscan4 is involved in telomere maintenance and long-term genomic stability in ES cells. Only 5% of ES cells express Zscan4 at a given time, but nearly all ES cells activate Zscan4 at least once during nine passages. The transient Zscan4-positive state is associated with rapid telomere extension by telomere recombination and upregulation of meiosis-specific homologous recombination genes, which encode proteins that are colocalized with ZSCAN4 on telomeres. Furthermore, Zscan4 knockdown shortens telomeres, increases karyotype abnormalities and spontaneous sister chromatid exchange, and slows down cell proliferation until reaching crisis by passage eight. Together, our data show a unique mode of genome maintenance in ES cells.
PMID: 20336070



Genes Cells. 2006 Nov;11(11):1305-15.
Rad54 is dispensable for the ALT pathway.
Akiyama K, Yusa K, Hashimoto H, Poonepalli A, Hande MP, Kakazu N, Takeda J, Tachibana M, Shinkai Y.
Department of Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Abstract
Some immortal cells use the alternative lengthening of telomeres (ALT) pathway to maintain their telomeres instead of telomerase. Previous studies revealed that homologous recombination (HR) contributes to the ALT pathway. To further elucidate molecular mechanisms, we inactivated Rad54 involved in HR, in mouse ALT embryonic stem (ES) cells. Although Rad54-deficient ALT ES cells showed radiosensitivity in line with expectation, cell growth and telomeres were maintained for more than 200 cell divisions. Furthermore, although MMC-stimulated sister chromatid exchange (SCE) was suppressed in the Rad54-deficient ALT ES cells, ALT-associated telomere SCE was not affected. This is the first genetic evidence that mouse Rad54 is dispensable for the ALT pathway.
PMID: 17054727


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