Regulator of telomere elongation helicase 1 (RTEL1) is an Fe-S cluster containing helicase that plays important roles in telomere DNA maintenance, DNA repair, and genome stability. It is a modular protein comprising a helicase domain, two tandem harmonin homology domains 1 & 2 (HHD1 and HHD2), and a RING domain. The RING domain interacts with telomere DNA binding protein TRF2 and helps in the recruitment of RTEL1 to the telomeres while the helicase domain disassembles telomere DNA t/D-loop and unwinds G-quadruplexes. The novel HHDs are predicted to mediate protein-protein interactions. Mutations in RTEL1 are associated with Hoyeraal-Hreidarsson syndrome and familial pulmonary fibrosis. Several of these mutations are found in the HHDs of RTEL1. In this study, we have carried out the structural characterization of HHDs of RTEL1. We report that human RTEL1 interacts and co-localizes with the replication protein A (RPA) in the cell. Using NMR spectroscopy and ITC experiments, we have shown that the HHD2 of RTEL1 interacts directly with the winged-helix 32C domain of RPA as well as DNA using an overlapping surface. These results establish an interplay among RTEL1, RPA, and DNA that has implications for understanding the role of RTEL1 in DNA replication, repair, and recombination processes.
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