DNA Repair 3 (2004) 919–925 Review The ATM-related kinase, hSMG-1, bridges genome and RNA surveillance pathways Robert T. Abraham ∗ Program in Signal Transduction Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92130, USA Available online 8 May 2004 Abstract Recent studies have identified, hSMG-1 as the newest member of the phosphoinositide 3-kinase(PI3-kinase)-related kinase (PIKK) family. The protein kinase activity of hSMG-1 resembles that of the related PIKK, ATM, both in terms of substrate specificity and its sensitivity to inhibition by the fungal metabolite wortmannin. hSMG-1 is the ortholog of a Caenorhabditis elegans protein, CeSMG-1, which has been genetically linked to a critical mRNA surveillance pathway termed nonsense-mediated decay (NMD). The function of NMD is to mark for rapid degradation mRNAs that bear a premature termination codon. Compelling evidence now indicates that hSMG-1 is also a central player in the NMD pathway in human cells. In addition, hSMG-1, like ATM, appears to be involved in the recognition and/or repair of damaged DNA in these cells. In this review, we introduce a model in which hSMG-1 teams with ATM and ATR to insure the overall quality of the transcriptome in human cells. © 2004 Elsevier B.V. All rights reserved. 1. Introduction Mammalian cells express six members of an unusual fam- ily of signaling proteins termed phosphoinositide 3-kinase (PI3-kinase)-related kinase (PIKKs) [1]. The present chap- ter will focus on the sixth and newest member of the mam- malian PIKK family, a protein serine–threonine kinase that was cloned independently by three laboratories, including our own. Based on its sequence and functional homology to the Caenorhabditis elegans protein, CeSMG-1 (see below for discussion), the human PIKK was named ‘human (h) SMG-1’ by two research groups [2,3]. Our laboratory des- ignated the same cDNA ‘ATX’, after noting the biochemical and functional similarity of the encoded protein to ATM and ATR [4]. To avoid confusion, however, we renamed our cDNA hSMG-1 in deference to the precedent litera- ture describing this new PIKK family member. Although much remains to be learned about hSMG-1 regulation and function, the available evidence suggests that this PIKK is centrally involved in both genome and RNA surveillance in mammalian cells. ∗ Tel.: +1-858-646-3182; fax: +1-858-713-6274. E-mail address: abraham@burnham.org (R.T. Abraham). 2. Structural and biochemical features of hSMG-1 As stated above, three independent groups, isolated hu- man cDNAs encoding the hSMG-1 polypeptide [2–4]. Each group found mRNAs encoding hSMG-1 proteins of vary- ing lengths, with the principal variation occurring at the 5 ′ -termini. Our hSMG-1 cDNA encodes a 3521-amino acid polypeptide with a deduced molecular mass of 395 kDa, and is eight amino acids shorter at the amino-terminus than the cDNA studied by Yamashita et al. [2]. Whether multiple forms of hSMG-1 with different amino-termini are actually expressed in mammalian cells remains unclear. Like all members of the PIKK family, the hSMG-1 pri- mary structure displays an extended amino-terminal region, which is followed by stretch of ∼300 amino acids that bears homology to the phosphotransferase domains of PI 3-kinases (Fig. 1). The distal carboxyl-terminus of hSMG-1 also expresses a relatively conserved, 35-amino acid motif termed as FATC (‘FAT’ stands for FRAP, ATM, and TR- RAP), which seems to be essential for the catalytic activity of the kinase domains in other PIKK family members ([5] and our unpublished observations). The big surprise with respect to hSMG-1 is the location of the kinase domain rel- ative to the FATC domain. In the other PIKK family mem- bers, the catalytic and FATC domains are separated by no more than a few hundred amino acids. In contrast, hSMG-1 1568-7864/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.dnarep.2004.04.003