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  • L002 mg Once apoptosis has been initiated the HMGA proteins

    2023-11-20

    Once apoptosis has been initiated the HMGA proteins themselves undergo marked changes in both the types and extent of their post-translational modifications (PTMs; review in [149,175]), some of which are likely correlated with alterations in chromatin structure. For example, the early stages of apoptosis are first accompanied by a global hyper-phosphorylation, which is quickly followed by a massive de-phosphorylation, of the total population of cellular HMGA proteins [41]. Since phosphorylation of HMGA proteins significantly reduces their binding affinity for A/T-rich DNA [109,136], hyper-phosphorylation likely results in partial displacement of HMGA proteins from DNA and the formation of a less condensed chromatin structure that is more easily digested by nucleases. Hypo-phosphorylated HMGA proteins, on the other hand, have an increased overall positive change that facilitates tighter DNA binding, chromatin condensation and placement of HMGA:DNA complexes into apoptotic bodies [41]. Other site-specific PTMs of HMGA proteins, such as acetylation of K60 of HMGA1b [50] and methylation of R25 of HMGA1a [146–148], have also been reported to occur during apoptosis but the function(s) of such modifications in the death process is unknown. In contrast to induction of apoptosis in normal cells, overexpression of HMGA proteins in some “pre-disposed” normal cells, as well as in immortalized cell lines that have already breached the senescence barrier, often has anti-apoptotic affects [85–87] and frequently induces overt cancerous transformation [34,72,168,169]. A variety of mechanisms contribute to anti-apoptosis including (i) binding of HMGA to HIPK2 kinase, a proapoptotic activator of p53, and chaperoning its relocalization from the nucleus to the cytoplasm [121]; (ii) binding of HMGA to p53 and interfering with p53-mediated transcription of apoptotic and L002 mg arrest effectors [54,120]; and (iii) cooperation of HMGA with other factors in the transcriptional activation of the p53 inhibitor MDM2 [120]. HMGA1 also regulates the transcriptional expression of a number of genes coding for micro-RNAs (miRNAs) [39], some of which (e.g., miR-29) could potentially interfere with apoptosis [83,101]. HMGA proteins have recently been directly implicated in the process of senescence, or aging, of normal cells. During senescence, a state of irreversible cell growth arrest, chromatin structure undergoes intricate and programmed global changes and these nuclear alterations are accompanied by equally complex alterations in the phenotypes of both aging cells and organisms [118]. A variety of molecular mechanisms can trigger senescence including DNA damage, acquisition of an active oncogene, telomere shortening and derepression of the INK4a/ARF locus and activation of the retinoblastoma (pRB) tumor suppressor pathways (reviewed in [36,113]). Together these mechanisms limit excessive or aberrant cellular proliferation and, as a consequence, senescence is thought to both protect organisms against the development of cancer and to be a component of aging [35,75,112]. Senescence is accompanied by marked changes in the epigenetic state of chromatin and by widespread nuclear heterochromatin formation [4,11,108,142,145]. For example, during senescence of human primary fibroblasts (e.g., WI38 and IMR90), chromosomes undergo profound condensation with each chromosome forming a punctuate heterochromatic domain called a senescence-associated heterochromatic focus (SAHF) [56,176]. The core histones of SAHFs are hypoacetylated due to increased levels of histone deacetylases (HDACs) in these structures [10]. Interestingly, the histones in SAHFs do not exhibit the typical PTM patterns that mark core histones of condensed mitotic chromosomes, apoptotic chromatin or transcriptionally inactive heterochromatin [56]. SAHFs do, however, contain histone H3 that is methylated on lysine 9 (H3K9Me), a modification that provides a docking site for repressive polycomb proteins which are known markers for constitutive heterochromatin. SAHFs also contain heterochromatin protein 1 (HP1) and the transcriptionally repressive histone variant macroH2A [56,106,176]. And, importantly for the present discussion, SAHFs are depleted in linker histone H1 and enriched for HMGA1 and HMGA2, proteins which have been demonstrated to be essential components of these heterochromatin structures [56,107,176].