Alkyltransferase-like proteins: molecular switches between DNA repair pathways

Abstract

Alkyltransferase-like proteins (ATLs) play a role in the protection of cells from the biological effects of DNA alkylation damage. Although ATLs share functional motifs with the DNA repair protein and cancer chemotherapy target O⁶-alkylguanine-DNA alkyltransferase, they lack the reactive cysteine residue required for alkyltransferase activity, so its mechanism for cell protection was previously unknown. Here we review recent advances in unraveling the enigmatic cellular protection provided by ATLs against the deleterious effects of DNA alkylation damage. We discuss exciting new evidence that ATLs aid in the repair of DNA O⁶-alkylguanine lesions through a novel repair cross-talk between DNA-alkylation base damage responses and the DNA nucleotide excision repair pathway.

Fig. 1

Chemical structures of the lesions recognized by ATL that are discussed in this review. The lesions are abbreviated as follows: O ⁶-mG, O ⁶-methylguanine; O ⁶-bG, O ⁶-benzylguanine; O ⁶-pobG, O ⁶-4-(3-pyridyl)-4-oxobutylguanine; O ⁶-btG, O ⁶-(4-bromothenyl)guanine; O ⁶-HOEtG, O ⁶-hydroxyethylguanine, O ⁶-1hpG, O ⁶-1-hydroxypropylguanine; O ⁶-2hpG, O ⁶-2-hydroxypropylguanine

Fig. 2

Proposed mechanisms for repair of O ⁶-alkylG (indicated by a red star)

Fig. 3

Sequence alignment of select ATLs (top) and AGTs (bottom), showing conservation of key tyrosine, arginine, and binding/active site residues, highlighted in black. The S. pombe Atl1-binding site and C-terminal loop is shaded gray

Fig. 4

Crystallographic structure of S. pombe Atl1, showing the overall fold. Key residues and loops are mapped to the web logo sequence alignment shown below

Fig. 5

Lesion binding by ATL and AGT. a Structural overlay of S. pombe Atl1- (gray, pdb 3gx4) and human AGT- (black, pdb 1t38) O ⁶-mG-DNA complexes. Key residues, loops, and O ⁶-mG from the ATL-DNA complex structure are indicated by arrows. b Stereo view of Atl1-O ⁶-mG DNA complex, with the binding pocket overlayed as a molecular surface. c Stereo view of hAGT-O ⁶-mG DNA complex, with the binding pocket overlayed as a molecular surface

Fig. 6

Possible participation of ATL in NER responses