NFBD1/MDC1 regulates ionizing radiation‐induced focus formation by DNA checkpoint signaling and repair factors
- 1 October 2003
- journal article
- Published by Wiley in The FASEB Journal
- Vol. 17 (13) , 1842-1848
- https://doi.org/10.1096/fj.03-0310com
Abstract
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 γ-H2AX. An overexpressed FHA domain-containing fragment of NFBD1 binds to endogenous NFBD1 and components of the MRN complex, but not to γ-H2AX. This fragment interferes with IRIF formation by endogenous NFBD1, MRE11, or NBS1. A BRCT domain-containing fragment of NFBD1 binds to γ-H2AX and 53BP1, but not to components of the MRN complex, and abolishes IRIF formation by NFBD1, MRE11, NBS1, 53BP1, CHK2 phospho-T68, γ-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.Keywords
Funding Information
- Research, Development and Engineering Command (17-98-1-8272, 17-01-1-0465)
- U.S. Public Health Service (R01CA82257)
This publication has 32 references indexed in Scilit:
- p53 Binding Protein 53BP1 Is Required for DNA Damage Responses and Tumor Suppression in MiceMolecular and Cellular Biology, 2003
- NFBD1, Like 53BP1, Is an Early and Redundant Transducer Mediating Chk2 Phosphorylation in Response to DNA DamageJournal of Biological Chemistry, 2003
- NFBD1/KIAA0170 Is a Chromatin-associated Protein Involved in DNA Damage Signaling PathwaysJournal of Biological Chemistry, 2003
- MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathwaysNature, 2003
- DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociationNature, 2003
- Checkpoint signalling: focusing on 53BP1Nature Cell Biology, 2002
- 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancerNature Cell Biology, 2002
- 53BP1, a Mediator of the DNA Damage CheckpointScience, 2002
- Budding Yeast Rad9 Is an ATP-Dependent Rad53 Activating MachinePublished by Elsevier ,2001
- Human keratinocytes and tumor-derived cell lines express alternatively spliced forms of transforming growth factor-α mRNA, encoding precursors lacking carboxyl-terminal valine residuesOncogene, 1999