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Published December 21, 1983 | public
Journal Article

Do stalled replication forks synthesize a specific alarmone?


Potential causes of premature arrest of a replication fork in vivo include an encounter with a chemical lesion in the DNA, inhibition of one of the essential enzymes of the fork, and spontaneous failure of the fork due to its finite degree of processivity. I suggest that a premature arrest of either a eukaryotic or prokaryotic replication fork induces it to enter a different state in which the fork synthesizes a specific signal nucleotide ("alarmone"). One function of the postulated new alarmone would be to increase the probability of re-initiation of DNA replication, either in cis (at an origin proximal to a site of the fork arrest) or in trans (at many different origins). An additional, mechanistically related function of the postulated alarmone could be to increase the probability of re-assembly of an arrested fork beyond an otherwise impassable DNA lesion. In case of multiple fork arrests, an alarmone-mediated increase in the probability of replicon reinitiation (disproportionate DNA replication) would result in gene amplification at many different loci, thereby increasing the probability of cell's survival in a cytotoxic medium. Other likely functions of a fork-produced alarmone may include stimulation of DNA repair pathways including excision repair. I review the experimental evidence which although indirect, is consistent with the idea of a fork-produced alarmone and specifically with the possibility that the postulated alarmone is diadenosine 5', 5′′′P¹, P⁴-tetraphosphate (Ap₄A) or a closely related adenylated nucleotide. The proposed hypothesis leads to specific, testable predictions; it also provides a unifying explanation for several hitherto unconnected observations on DNA replication, repair and amplification.

Additional Information

© 1983 Academic Press. (Received 22 April 1983, and in revised form 29 August 1983) I thank Daniel Finley, James Barsoum, Igor Roninson and Paul Swerdlow for their comments on the manuscript. Experimental work in the author's laboratory is supported by grants from the National Cancer Institute and the National Institute of General Medical Sciences.

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