Abstract
DNA alkylguanine DNA alkyltransferases (AGTs) are evolutionary conserved proteins that repair alkylation damage in DNA, counteracting the effects of agents inducing such lesions. Over the last years AGTs have raised considerable interest for both the peculiarity of their molecular mechanism and their relevance in cancer biology. AGT knock out mice show increased tumour incidence in response to alkylating agents, and over-expression of the human AGT protein in cancer cells is frequently associated with resistance to alkylating chemotherapy. While all data available point to a function of AGT proteins in the cell response to alkylation lesions, we report for the first time that one of the two AGT paralogs of the model organism C. elegans, called AGT-2, also plays unexpected roles in meiosis and early development under physiological conditions. Our data suggest a role for AGT-2 in conversion of homologous recombination intermediates into post-strand exchange products in meiosis, and show that agt-2 gene down-regulation, or treatment of animals with an AGT inhibitor results in increased number of germ cells that are incompatible with producing viable offspring and are eliminated by apoptosis. These results suggest possible functions for AGTs in cell processes distinct from repair of alkylating damage.
Highlights
Www.nature.com/scientificreports most pathways and key factors in these processes are conserved from worms to humans
AGT paralogs, the putative AGT-1 protein (ORF Y62E10A.5) is structurally similar to other members of this protein family, whereas AGT-2 (ORF F09E5.13) predicted primary sequence is highly divergent[29]. This 274 amino acid protein displays significant similarities to canonical AGTs only in the region from residues 62 to 96, which contains the cysteine acceptor site and the DNA helix-turn-helix (HTH) binding motif; even in this region, the active site motif is –PCHP– instead of –PCHR– found in hAGT, and few of the residues in the presumptive HTH motif are identical to the corresponding residues in hAGT (Fig. 1A and Supplementary Fig. 2A)
These results suggest the elevated apoptosis levels observed in the agt-2 mutant or when the wild type was treated with the AGT inhibitor depend on inefficient repair of meiotic double strand breaks (DSBs), which trigger the DNA damage checkpoint
Summary
Www.nature.com/scientificreports most pathways and key factors in these processes are conserved from worms to humans. These include homologous recombination (HR), non-homologous end-joining (NHEJ), mismatch repair, nucleotide excision repair, interstrand crosslinking repair[18]; orthologs of several human disease-linked genes belonging to these pathways are conserved in the nematode, including the DNA damage checkpoint gene ATR (atl-1 in C. elegans)[19], the breast cancer predisposition BRCA1 and BRCA2 genes (brc-1 and brc-2, respectively)[20,21,22,23], the Fanconi Anemia FANCJ, FANCD-2, FANC-I and FANCM genes (dog-1, fcd-2, fnci-1, fncm-1, respectively)[24,25,26,27,28], making C. elegans a useful model to study disease-related genes. Our data reveal that the agt-2 gene plays unexpected roles in the nematode meiosis and early development under physiological conditions
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