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Department of Pathology, School of Medicine, Yale University, New Haven, Connecticut, USA
1Correspondence: Department of Pathology, School of Medicine, Yale University, 310 Cedar St., BML342, New Haven, CT 06510, USA. E-mail: df.stern{at}yale.edu
NFBD1/MDC1 (mediator of DNA damage checkpoint 1) is a nuclear factor with an amino-terminal FHA (forkhead-associated) domain and a tandem repeat of BRCT (breast cancer susceptibility gene-1 carboxyl terminus) domains. We have previously shown that NFBD1 is an early participant in DNA damage signaling pathways and that ionizing radiation-induced nuclear foci (IRIF) of NFBD1 colocalize with several DNA checkpoint signaling and repair factors. We report here that NFBD1 physically associates with ATM, p53, components of the MRE11-RAD50-NBS1 (MRN) complex, and 
-H2AX. An overexpressed FHA domain-containing fragment of NFBD1 binds to endogenous NFBD1 and components of the MRN complex, but not to -H2AX. This fragment interferes with IRIF formation by endogenous NFBD1, MRE11, or NBS1. A BRCT domain-containing fragment of NFBD1 binds to -H2AX and 53BP1, but not to components of the MRN complex, and abolishes IRIF formation by NFBD1, MRE11, NBS1, 53BP1, CHK2 phospho-T68, -H2AX, and possible ATM/ATR substrates recognized by anti-phospho-SQ/TQ antibody. These results suggest that NFBD1 is an ATM/ATR-dependent organizer that recruits DNA checkpoint signaling and repair proteins to the sites of DNA damage.—Xu, X., Stern, D. F. NFBD1/MDC1 regulates ionizing radiation-induced focus formation of DNA checkpoint signaling and repair factors.
Key Words: 53BP1 • -H2AX • MRE11 complex • ATM/ATR substrates • assembly of ionizing radiation-induced foci
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