Journal
NUCLEIC ACIDS RESEARCH
Volume 32, Issue 12, Pages 3743-3751Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkh691
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Funding
- NCI NIH HHS [R01 CA043322, CA77693, R01 CA077693, CA43322] Funding Source: Medline
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For cells on the path to carcinogenesis, the key to unlimited growth potential lies in overcoming the steady loss of telomeric sequence commonly referred to as the 'end-replication problem' that occurs with each cell division. Most human tumors have reactivated telomerase, a specialized reverse transcriptase, that directs RNA-templated addition of telomeric repeats on to chromosomal termini. However, similar to10% of tumors maintain their telomeres through a recombination-based mechanism, termed alternative lengthening of telomeres or ALT. Here we demonstrate that telomeric DNA undergoes a high rate of a particular type of recombination visualized cytogenetically as sister chromatid exchange (SCE), and that this rate is dependent on genotype. A novel model of ALT is presented in which it is argued that telomeric exchanges, if they are unequal and occur at a sufficiently high frequency, will allow cells to proliferate indefinitely without polymerase-mediated extension of telomeric sequence.
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