Nuclear DEAF-1-related (NUDR) Protein Contains a Novel DNA Binding Domain and Represses Transcription of the Heterogeneous Nuclear Ribonucleoprotein A2/B1 Promoter

Abstract

Nuclear DEAF-1-related (NUDR) protein is a novel transcriptional regulator with sequence similarity to developmental and oncogenic proteins. NUDR protein deletions were used to localize the DNA binding domain between amino acids 167 and 368, and site-specific DNA photocross-linking indicated at least two sites of protein-DNA contact within this domain. The DNA binding domain contains a proline-rich region and a region with similarity to a Myc-type helix-loop-helix domain but does not include the zinc finger motif at the C terminus. Deoxyribonuclease I protection assays confirmed the presence of multiple NUDR binding motifs (TTC(C/G)G) in the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) promoter and also in the 5-untranslated region (UTR) of hNUDR cDNA. NUDR produced a 65-70% repression of the hnRNP A2/B1 promoter activity, and NUDR binding motifs in the 5-UTR were found to mediate this repression. NUDR-dependent repression was also observed when the 5-UTR of NUDR was placed onto a heterologous thymidine kinase promoter in an analogous 5-UTR position but not when placed upstream of transcription initiation. These results suggest that NUDR may regulate the in vivo expression of hnRNP A2/B1 and NUDR genes and imply that inactivation of NUDR could contribute to the overexpression of hnRNP A2/B1 observed in some human cancers.

Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire

“…The G228W mutation occurs in the Aire SAND domain, a known DNA-binding domain for other SAND domain-containing proteins (15,48,49). However, Aire does not contain the KWDK DNA-binding motif in the SAND domain that the other SAND domain-containing family members harbor.…”

Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers

“…BLU contains a predicted MYND domain at its Cterminus that shares 45% identity with the MYND domains found in important transcription regulatory proteins such as ETO(MTG8) (Wolford and Prochazka, 1998), suppressins (LeBoeuf et al, 1998), BS69 (Masselink and Bernards, 2000) and the Drosophila developmental proteins DEAF-1 (Michelson et al, 1999) and nervy (Feinstein et al, 1995). The MYND motif is essential to the function of many of these proteins.…”

PDCD2 is a negative regulator of HCF-1 (C1)

“…Apart from this domain, these proteins are unrelated in sequence to ETO. However, NUDR has been shown to repress transcription, DEAF-1 regulates transcription, suppressin is a growth suppressor of unknown mechanism, and MTGR1, like ETO, has been shown to be involved in myeloid malignancies through translocations with chromosome 21 (LeBoeuf et al, 1998;Michelson et al, 1999;Morohoshi et al, 2000;Sugihara et al, 1998).…”