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Yasutoshi Tatsumi^1,a,, Kai Ezura^1,, Kazumasa Yoshida¹, Takashi Yugawa¹, Mako Narisawa-Saito¹, Tohru Kiyono¹, Satoshi Ohta^2,b, Chikashi Obuse^2,3 and Masatoshi Fujita^1,*

¹ Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuohku, Tokyo 104-0045, Japan
² Nara Institute of Science and Technology, Takayama, Ikoma, Nara 630-0101, Japan
³ Faculty of Advanced Life Science, Hokkaido University, Kita-21, Nishi-11, Sapporo 001-0021, Japan

The origin recognition complex (ORC) binds to replication origins to regulate the cell cycle-dependent assembly of pre-replication complexes (pre-RCs). We have found a novel link between pre-RC assembly regulation and telomere homeostasis in human cells. Biochemical analyses showed that human ORC binds to TRF2, a telomere sequence-binding protein that protects telomeres and functions in telomere length homeostasis, via the ORC1 subunit. Immunostaining further revealed that ORC and TRF2 partially co-localize in nuclei, whereas chromatin immunoprecipitation analyses confirmed that pre-RCs are assembled at telomeres in a cell cycle-dependent manner. Over-expression of TRF2 stimulated ORC and MCM binding to chromatin and RNAi-directed TRF2 silencing resulted in reduced ORC binding and pre-RC assembly at telomeres. As expected from previous reports, TRF2 silencing induced telomere elongation. Interestingly, ORC1 silencing by RNAi weakened the TRF2 binding as well as the pre-RC assembly at telomeres, suggesting that ORC and TRF2 interact with each other to achieve stable binding. Furthermore, ORC1 silencing also resulted in modest telomere elongation. These data suggest that ORC might be involved in telomere homeostasis in human cells.

^aPresent address: Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.

^bPresent address: Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.

These authors equally contributed to this work.

^* Correspondence: mafujita{at}ncc.go.jp