Figure 2

Proposed roles for FUS/TLS include 1) association with TBP within the TFIID complex as a participant in the general transcriptional machinery and 2) binding to long introns in a sawtooth-like pattern, consistent with co-transcriptional deposition. Both TDP-43 and FUS/TLS 3) associate with promoter regions. TDP-43 binds single-stranded TG-rich elements in promoter regions thereby blocking transcription of the downstream gene. In response to DNA damage, FUS/TLS is recruited in the promoter region of cyclin D1 (CCND1) by sense and antisense noncoding RNAs (ncRNAs) and represses CCND1 transcription. BothTDP-43 and FUS/TLS 4) bind long intron-containing RNAs, thereby sustaining their levels. 5) TDP-43 and FUS/TLS control the levels of >950 or >370 RNAs, respectively, either via direct binding or indirectly. TDP-43 and FUS/TLS 6) bind long non-coding RNAs, 7) complex with Drosha (consistent with an involvement in miRNA processing), and 8) bind 3′UTRs of a large number of mRNAs. Both TDP-43 and FUS/TLS shuttle between the nucleus and the cytosol and are incorporated into 9) transporting RNA granules and 10) stress granules, in which they form complexes with mRNAs and other RNA binding proteins.