Role of Rap1 in DNA damage response: implications in stem cell homeostasis and cancer

•Mammalian Rap1 protein acts as an adaptor in functional complexes formed under various physiological conditions.•Rap1 plays an important role in the DNA damage response at telomeric and nontelomeric regions, thus maintaining genome stability.•The role of Rap1 in the DNA damage response has implications for stem cell survival, oncogenesis, and chemotherapeutic response. Mammalian Rap1 is a part of the telomere binding complex named shelterin and is one of the most conserved telomeric proteins. With its essential requirement in lower species to its becoming necessary in higher species, it appears to have gained and lost several functions simultaneously evolving with telomeres. Mammalian Rap1 has been reported to play a role in inflammation, metabolism, and oxidative stress. Mammalian Rap1 has also been found to regulate DNA damage response from telomeres in senescent cells. Recently our group uncovered its novel role in stem cell maintenance, and modulation of the chemotherapeutic response. Mechanistically it was found to function as an adaptor via protein–protein interactions and to modulate the response to DNA damage. In the current review we highlight newly identified functions of Rap1 in regulating telomeric and general DNA damage response with its impact at the cellular and organismal levels.