Transcription factor Sp1 promotes chromatin remodeling at dna double-strand breaks

Kate Beishline

doi:10.17918/00000472

Specificity Protein 1 (Sp1) is ubiquitously expressed transcription factor that is over expressed in a number of cancers. Due to Sp1's regulatory control over a number of cellular growth and metabolic proteins, the protein has been proposed as a potential therapeutic target, to suppress tumor growth and induce cell death. Despite the vast knowledge of Sp1's transcriptional functions, little is known about non-transcriptional functions of Sp1. We have determined Sp1 is required for Double Strand Break (DSB) repair. DNA damage is intimately associated with cancer and aging. The DNA damage response is complex, with pathways that sense lesions, signal cell-cycle arrest, and repair damaged DNA to prevent mutations. A number of transcription factors like SO have been implicated in DNA repair pathways. SO is phosphorylated in response to DNA damage and recruited to sites of DSBs. Using basic molecular biology techniques we were able to determine the N-terminal 182 amino acids of Sp1 are sufficient for localization to DSBs and while it retains no transcriptional activity, this domain is sufficient to rescue the defect in repair of site-specific DSBs in Sp1-depleted cells, suggesting Sp1 plays a direct role in repair. We have shown a unique interaction between Sp1 and the MRN complex member, Nbs1, which likely promotes its recruitment. Sp1 mediates chromatin remodeling at promoters and our data suggest that Sp1 plays a similar role at DSBs. We have shown that the Sp1 is required for recruitment of the acetyl-transferase p300 to break sites, which acetylates histone H3 on Lys18. This modification, and others promote nucleosome displacement at break sites to allow for repair factor recruitment. Sp1 mediated modifications of chromatin may participate in cellular signaling that determines if the cells uses non-homologous end-joining or homologous recombination to repair breaks. Sp1 expression is modulated in multiple cancers and investigating the role of Sp1 in DNA repair is essential for a mechanistic understanding of damage signaling in tumors. This study will provide insights into genomic instability in these cancers, how they respond to damage inducing chemotherapeutics, as well as novel therapeutic targets in cancers with abnormal Sp1 levels.

Transcription factor Sp1 promotes chromatin remodeling at dna double-strand breaks

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Transcription factor Sp1 promotes chromatin remodeling at dna double-strand breaks

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