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  • Formation of SAHFs in human cells is a dynamic

    2022-11-25

    Formation of SAHFs in human MK-8745 is a dynamic and multifaceted process that is largely dependent on the p16/pRB ras-induced senescence pathway [108]. Many details remain to be elucidated but formation appears to be driven by a complex of histone chaperones (HIRA and ASF1a), a pRB/hBrm/HDAC1/HP1β chromatin remodeling complex plus an additional chaperone protein (HIRA-3) that physically links these two complexes together and coordinates their activity [4,106,177]. It has been proposed that the hBrm component of the remodeling complex is required for incorporation of histone variants such as macroH2A in SAHFs [10]. It is not known whether the hBrm-containing complex, the HIRA-containing complex or another yet unidentified complex contributes to the recruitment of HMGA proteins to SAHFs. What has been demonstrated, however, is that incorporation of HMGA proteins into SAHFs is linked to simultaneous displacement of histone H1 [56]. As previously mentioned, HMGA proteins can out-compete histone H1 for binding to a variety of different types of DNA substrates [66,68,178]. It has been suggested, therefore, that SAHF formation is a novel type of chromatin condensation involving alterations in linker DNA-binding proteins with HMGA out-competing and replacing histone H1 [56]. It should be noted that this model for SAHF formation is very similar to the previously discussed model proposed by Laemmli's group [78,82,178] except that, in this case, HMGA displacement of histone H1 leads to chromosome condensation rather than to chromatin domain de-condensation and “opening”. Since HMGAs are among the most highly modified proteins in the nucleus and such PTMs influence their substrate binding characteristics (review in [135,175]), these two different effects of HMGA proteins on chromatin structure could well be due to differences in the types of biochemical modifications present on the proteins in SAHFs and in activated chromatin domains. In light of the fact that overexpression of HMGA genes causes neoplastic transformation of cells in vitro and also induces tumors in transgenic mice in vivo[171,49,51], the specific accumulation of HMGAs on chromatin during senescence and a requirement for these proteins in SAHF formation were initially perplexing [107]. Although there is still no completely satisfactory answer to this apparent paradox, available data derived from experiments involving knock-down and knock-in of various SAHF components in transfected cells, combined with the use of drugs that compete for HMGA binding to the minor groove A/T-rich DNA (summarized in [106]), have suggested that HMGA contributes to SAHF formation by modulating higher-order chromatin structure and limiting its accessibility to transcription factors. Thus, just as in the case of apoptosis, HMGA proteins can be either pro- or anti-oncogenic, depending on the cellular context and the biochemical modification state of the proteins. Consistent with this ying-yang view, it has been reported that malignant hematologic tumors develop in both transgenic mice that overexpressing HMGA1 [49] and in Hmga1 knock-out mice that are devoid of this protein [52]. HMGA proteins also influences the capacity of cells to repair damaged DNA by affecting chromatin structure at both the genome-wide and gene-specific levels [97,134]. HMGA overexpression sensitizes cancerous cells to killing by various genotoxic agents such as UV light, cisplatin, hydrogen peroxide, menadione and methymethanesulfonate (MMS) [2,98,134]. In the case of UV light, which induces backbone-distorting cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidone (6-4-PP) photoproducts into DNA, the increased killing has been causally linked to inhibition of the nucleotide excision repair (NER) pathway that removes bulky lesions from damaged DNA [2,3,97]. This repair inhibition is mediated by (i) binding of HMGA protein directly to CPD and 6-4PP lesions and preventing access of NER repair proteins by steric hindrance [2] and (ii) specific binding of HMGA to the promoter region of XPA, a gene whose protein product is essential for efficient NER, and inhibiting its transcription [2]. It seems likely that HMGA overexpression also inhibits repair of non-bulky lesions that are removed by the base excision repair (BER) pathway by similar mechanisms [98,134].