Mol._Cell._Biol.-2009-Reynolds-1354-62.pdf (810.42 kB)
Defective DNA ligation during short-patch single-strand break repair in ataxia oculomotor apraxia 1
journal contribution
posted on 2023-06-08, 12:36 authored by John J Reynolds, Sherif F El-Khamisy, Sachin Katyal, Peter Clements, Peter J McKinnon, Keith CaldecottKeith CaldecottAtaxia oculomotor apraxia 1 (AOA1) results from mutations in aprataxin, a component of DNA strand break repair that removes AMP from 5' termini. Despite this, global rates of chromosomal strand break repair are normal in a variety of AOA1 and other aprataxin-defective cells. Here we show that short-patch single-strand break repair (SSBR) in AOA1 cell extracts bypasses the point of aprataxin action at oxidative breaks and stalls at the final step of DNA ligation, resulting in the accumulation of adenylated DNA nicks. Strikingly, this defect results from insufficient levels of nonadenylated DNA ligase, and short-patch SSBR can be restored in AOA1 extracts, independently of aprataxin, by the addition of recombinant DNA ligase. Since adenylated nicks are substrates for long-patch SSBR, we reasoned that this pathway might in part explain the apparent absence of a chromosomal SSBR defect in aprataxin-defective cells. Indeed, whereas chemical inhibition of long-patch repair did not affect SSBR rates in wild-type mouse neural astrocytes, it uncovered a significant defect in Aptx(-/-) neural astrocytes. These data demonstrate that aprataxin participates in chromosomal SSBR in vivo and suggest that short-patch SSBR arrests in AOA1 because of insufficient nonadenylated DNA ligase.
History
Publication status
- Published
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- Published version
Journal
Molecular and Cellular BiologyISSN
0270-7306Publisher
American Society for MicrobiologyExternal DOI
Issue
5Volume
29Page range
1354-1362Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2012-11-01First Open Access (FOA) Date
2016-03-22First Compliant Deposit (FCD) Date
2016-11-16Usage metrics
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