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Molecular and Cellular Biology, May 2007, p. 3793-3803, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02269-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

APLF (C2orf13) Is a Novel Human Protein Involved in the Cellular Response to Chromosomal DNA Strand Breaks{triangledown}

Natasha Iles,1,{dagger} Stuart Rulten,1,{dagger} Sherif F. El-Khamisy,1,2 and Keith W. Caldecott1*

Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, Sussex BN25 3EU, United Kingdom,1 Biochemistry Department, Faculty of Pharmacy, Aim Shams University, P.O. Box 11566, Cairo, Egypt2

Received 5 December 2006/ Returned for modification 4 January 2007/ Accepted 5 March 2007

Aprataxin and polynucleotide kinase (PNK) are DNA end processing factors that are recruited into the DNA single- and double-strand break repair machinery through phosphorylation-specific interactions with XRCC1 and XRCC4, respectively. These interactions are mediated through a divergent class of forkhead-associated (FHA) domain that binds to peptide sequences in XRCC1 and XRCC4 that are phosphorylated by casein kinase 2 (CK2). Here, we identify the product of the uncharacterized open reading frame C2orf13 as a novel member of this FHA domain family of proteins and we denote this protein APLF (aprataxin- and PNK-like factor). We show that APLF interacts with XRCC1 in vivo and in vitro in a manner that is stimulated by CK2. Yeast two-hybrid analyses suggest that APLF also interacts with the double-strand break repair proteins XRCC4 and XRCC5 (Ku86). We also show that endogenous and yellow fluorescent protein-tagged APLF accumulates at sites of H2O2 or UVA laser-induced chromosomal DNA damage and that this is achieved through at least two mechanisms: one that requires the FHA domain-mediated interaction with XRCC1 and a second that is independent of XRCC1 but requires a novel type of zinc finger motif located at the C terminus of APLF. Finally, we demonstrate that APLF is phosphorylated in a DNA damage- and ATM-dependent manner and that the depletion of APLF from noncycling human SH-SY5Y neuroblastoma cells reduces rates of chromosomal DNA strand break repair following ionizing radiation. These data identify APLF as a novel component of the cellular response to DNA strand breaks in human cells.

* Corresponding author. Mailing address: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, Sussex BN1 9RQ, United Kingdom. Phone: 44 (0) 1273 877519. Fax: 44 (0) 1273 678121. E-mail: k.w.caldecott{at}sussex.ac.uk

{triangledown} Published ahead of print on 12 March 2007.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, May 2007, p. 3793-3803, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02269-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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