Stress Granules Sequestration of HSF1 and Splicing Factors

In primate cells exposed to a stress, a large fraction of HSF1 was observed to rapidly redistribute from the nucleoplasm (and cytoplasm) to a small number of subnuclear structures referred to as stress granules (Cotto et al. 1997). Although it soon became clear that stress granules are not associated with genes for major hsp genes (Jolly et al. 1997), it only recently could be shown that the structures form on a particular heterochromatic region of (human) chromosome 9 (9q12) to which HSF1 binds (Jolly et al. 2002). Overexpression of Hsp70 prevents the concentration of HSF1 in stress granules (Jolly et al. 2002). Within these structures, HSF1 activates transcription of satellite III repeats by RNA polymerase II (Jolly et al. 2004; Rizzi et al. 2004). The transcripts formed remain stably associated with the 9q12 region. Stress granules are also sites of sequestration of specific splicing factors such as hSF2/ASF and hSRp30c, which is dependent on HSF1 and satellite III transcripts (Metz et al. 2004, and references cited therein). Although this remains speculative, it may be hypothesized that sequestration of the majority of stress-activated HSF1

molecules in stress granules will alter the dynamics of hsp gene expression. In terms of feedback regulation, the degree of competition by nonnative proteins for Hsp70 during stress recovery may influence HSF1 sequestration in stress granules, which in turn may affect expression from hsp genes. The expression of proteins from non-hsp genes may also be impacted owing to the sequestration of certain splicing factors in stress granules.

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