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Defective DNA ligation during short-patch single-strand break repair in ataxia oculomotor apraxia 1

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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 Caldecott
Ataxia 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

File Version

  • Published version

Journal

Molecular and Cellular Biology

ISSN

0270-7306

Publisher

American Society for Microbiology

Issue

5

Volume

29

Page range

1354-1362

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2012-11-01

First Open Access (FOA) Date

2016-03-22

First Compliant Deposit (FCD) Date

2016-11-16

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