Species variations in XRCC1 recruitment strategies for FHA domain-containing proteins

DNA repair scaffolds XRCC1 and XRCC4 utilize a phosphopeptide FHA domain binding motif (FBM) of the form Y-x-x-pS-pT-D-E that supports recruitment of three identified FHA domain-containing DNA repair proteins: polynucleotide kinase/phosphatase (PNKP), aprataxin (APTX), and a third protein, APLF, that functions as a scaffold in support of non-homologous end joining (NHEJ). Mammalian dimeric XRCC4 is able to interact with two of these proteins at any given time, while monomeric XRCC1 binds only one. However, sequence analysis indicates that amphibian and teleost XRCC1 generally contain two FHA binding motifs. X1-FBM1, is similar to the single mammalian XRCC1 FBM and probably functions similarly. X1-FBM2, is more similar to mammalian XRCC4 FBM; it is located closer to the XRCC1 BRCT1 domain and probably is less discriminating among its three likely binding partners. Availability of an additional PNKP or APTX recruitment motif may alleviate the bottleneck that results from using a single FBM motif for recruitment of multiple repair factors. Alternatively, recruitment of APLF by X1-FBM2 may function to rescue a misdirected or unsuccessful SSB repair response by redirecting the damaged DNA to the NHEJ pathway, - a need that results from the ambiguity of the PARP1 signal regarding the nature of the damage. Evaluation of XRCC4 FBMs in acanthomorphs, which account for a majority of the reported teleost sequences, reveals the presence of an additional XRCC4-like paralog, distinct from other previously described members of the XRCC4 superfamily. The FBM is typically absent in acanthomorph XRCC4, but present in the XRCC4-like paralog. Modeling suggests that XRCC4 and its paralog may form homodimers or XRCC4-XRCC4-like heterodimers.