Alternative lengthening of telomeres: models, mechanisms and implications
Top Cited Papers
- 30 March 2010
- journal article
- review article
- Published by Springer Science and Business Media LLC in Nature Reviews Genetics
- Vol. 11 (5), 319-330
- https://doi.org/10.1038/nrg2763
Abstract
About 10% of all cancers, including some that have a particularly poor prognosis, use the alternative lengthening of telomeres (ALT) pathway to prevent the telomere shortening that accompanies proliferation of normal cells. ALT-positive cells commonly have a number of unusual characteristics, including telomeric DNA that is separated from chromosome ends. This extrachromosomal telomeric DNA may be linear or circular. Partially single-stranded circles of telomeric DNA in which the C-rich (AATCCC)n strand is essentially intact and the G-rich (TTAGGG)n strand is gapped seem to be the best of the known markers for ALT. The quantity of this 'C-circle' DNA correlates well with the amount of ALT activity. Telomere elongation in ALT cells involves homologous recombination. The experimental evidence fits best with a model for ALT in which telomeric 3′ overhangs become extended by invading other telomeric DNA and using it as a template for DNA replication. The other telomeric DNA can be: part of the same telomere (through telomere-loop formation); in a sister chromatid; in the telomere of another chromosome; or in one of the forms of extrachromosomal telomeric DNA. Proteins that are thought to be required for ALT include the homologous recombination protein complexes MRN (which is made up of meiotic recombination 11 (MRE11, also known as MRE11A), RAD50 and Nijmegen breakage syndrome 1 (NBS1, also known as NBN)) and structural maintenance of chromosomes 5 (SMC5)–SMC6, and proteins, such as flap endonuclease 1 (FEN1), MUS81, Fanconi anaemia group D2 (FANCD2) and Fanconi anaemia group A (FANCA), that may be required for recombination-dependent restart of stalled telomeric DNA replication. Promyelocytic leukaemia (PML) bodies containing telomeric DNA are characteristic of ALT cells, and are referred to as ALT-associated PML bodies (APBs). Large APBs seem to be associated with senescence of ALT cells and sequestration of extrachromosomal DNA, but we speculate that smaller APBs may be sites at which telomere lengthening occurs. In ALT cells, many of the telomeres elicit a DNA-damage response but repress chromosome end-to-end fusions. This telomere state, which is intermediate between the fully capped and uncapped fusogenic telomere states, may reflect a structural change that is permissive for recombination-mediated telomere replication.Keywords
This publication has 119 references indexed in Scilit:
- Human RAP1 inhibits non-homologous end joining at telomeresThe EMBO Journal, 2009
- Multiple roles for MRE11 at uncapped telomeresNature, 2009
- Telomere recombination requires the MUS81 endonucleaseNature, 2009
- Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: Mechanistic insightsMutation Research, 2009
- Control of telomere length by a trimming mechanism that involves generation of t-circlesThe EMBO Journal, 2009
- TRF2 promotes, remodels and protects telomeric Holliday junctionsThe EMBO Journal, 2009
- Topoisomerase IIIα is required for normal proliferation and telomere stability in alternative lengthening of telomeresThe EMBO Journal, 2008
- Flap Endonuclease 1 Contributes to Telomere StabilityCurrent Biology, 2008
- A DNA damage checkpoint response in telomere-initiated senescenceNature, 2003
- Telomeres shorten during ageing of human fibroblastsNature, 1990