NFBD1/Mdc1 mediates ATR-dependent DNA damage response

Aimin Peng, Phang Lang Chen

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Budding yeast Rad9 (scRad9) plays a central role in mediating Mec1-dependent phosphorylation by recruiting its downstream substrates. The human scRad9 orthologues 53BP1 and NFBD1 associate with ionizing radiation-induced foci (IRIF) at sites of DNA repair. RNAi-based gene silencing of 53BP1 or NFBD1 has shown impaired phosphorylation of SQ/TQ [ataxia-telangiectasia mutated/ATM and Rad3-related (ATM/ATR) substrates] at IRIF, intra-S, and G2-M checkpoints and has thereby revealed essential roles for 53BP1 and NFBD1 in the DNA damage signaling pathway. Whether 53BP1 and NFBD1 are required for activation of kinases and/or for recruitment of substrates at IRIF, however, is not clear. Here we show that both 53BP1 and NFBD1 are required for recruitment of ATR to DNA damage sites, as well as for ATR-dependent phosphorylation in response to DNA damage. NFBD1 is not required for ssDNA generation at DNA damage sites and is not recruited by replication protein A (RPA)-coated ssDNA. We therefore show that recruitment of NFBD1 and/or 53BP1, the factors downstream of H2AX, is independent of ssDNA generation and RPA coating, whereas both ssDNA and RPA coating play key roles in regulation of the ATR-dependent pathway. These novel findings help clarify where NFBD1 functions in DNA damage early responses.

Original languageEnglish (US)
Pages (from-to)1158-1163
Number of pages6
JournalCancer Research
Volume65
Issue number4
DOIs
StatePublished - Feb 15 2005

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DNA Damage
Replication Protein A
Ionizing Radiation
Phosphorylation
Ataxia Telangiectasia
Saccharomycetales
Gene Silencing
RNA Interference
DNA Repair
Phosphotransferases

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

NFBD1/Mdc1 mediates ATR-dependent DNA damage response. / Peng, Aimin; Chen, Phang Lang.

In: Cancer Research, Vol. 65, No. 4, 15.02.2005, p. 1158-1163.

Research output: Contribution to journalArticle

Peng, Aimin ; Chen, Phang Lang. / NFBD1/Mdc1 mediates ATR-dependent DNA damage response. In: Cancer Research. 2005 ; Vol. 65, No. 4. pp. 1158-1163.
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