RPA-Binding Protein ETAA1 Is an ATR Activator Involved in DNA Replication Stress Response.
ETAA1 (Ewing tumor-associated antigen 1), also known as ETAA16, was identified as a tumor-specific antigen in the Ewing family of tumors. However, the biological function of this protein remains unknown. Here, we report the identification of ETAA1 as a DNA replication stress response protein. ETAA1 specifically interacts with RPA (Replication protein A) via two conserved RPA-binding domains and is therefore recruited to stalled replication forks. Interestingly, further analysis of ETAA1 function revealed that ETAA1 participates in the activation of ATR signaling pathway via a conserved ATR-activating domain (AAD) located near its N terminus. Importantly, we demonstrate that both RPA binding and ATR activation are required for ETAA1 function at stalled replication forks to maintain genome stability. Therefore, our data suggest that ETAA1 is a new ATR activator involved in replication checkpoint control.
Department of Radiation Oncology, Center for Radiological Research, Columbia University Medical Center, 630 West 168(th) Street, New York, NY 10032, USA.
Yuan-Cho
YC
Lee
Department of Radiation Oncology, Center for Radiological Research, Columbia University Medical Center, 630 West 168(th) Street, New York, NY 10032, USA.
Qing
Q
Zhou
Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: jchen8@mdanderson.org.
Junjie
J
Chen
Department of Radiation Oncology, Center for Radiological Research, Columbia University Medical Center, 630 West 168(th) Street, New York, NY 10032, USA. Electronic address: jy2754@cumc.columbia.edu.
Jingsong
J
Yuan
D000818:Animals; D000906:Antibodies; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D004249:DNA Damage; D004261:DNA Replication / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000072417:Protein Domains; D011817:Rabbits; D013312:Stress, Physiological
D000906:Antibodies; D000954:Antigens, Surface; C508506:ETAA1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
AAD; ATR; DNA damage response; DNA repair; DNA replication stress; ETAA1; RAD9-RAD1-HUS1 complex; TOPBP1; ionizing radiation