The transcriptional cofactor MCAF1/ATF7IP is involved in histone gene expression and cellular senescence

• Published in: PloS one Vol. 8; no. 7; p. e68478
• Main Authors: Sasai, Nobuhiro, Saitoh, Noriko, Saitoh, Hisato, Nakao, Mitsuyoshi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.07.2013; Public Library of Science (PLoS)
• Subjects: Biology; Cell cycle; Cell Cycle Checkpoints - genetics; Cell Line; Cellular Senescence - genetics; Deoxyribonucleic acid; DNA; Embryology; Epigenetics; Fibroblasts; Gene expression; Gene Expression Regulation; Gene Knockdown Techniques; Histone H1; Histones; Histones - genetics; Humans; Nuclear Proteins - metabolism; Promyelocytic Leukemia Protein; Protein Binding; Protein Transport; Proteins; RNA polymerase; Senescence; Small Ubiquitin-Related Modifier Proteins - metabolism; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - metabolism; Ubiquitins - metabolism; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068478

Cellular senescence is post-mitotic or oncogene-induced events combined with nuclear remodeling. MCAF1 (also known as hAM or ATF7IP), a transcriptional cofactor that is overexpressed in various cancers, functions in gene activation or repression, depending on interacting partners. In this study, we found that MCAF1 localizes to PML nuclear bodies in human fibroblasts and non-cancerous cells. Interestingly, depletion of MCAF1 in fibroblasts induced premature senescence that was characterized by cell cycle arrest, SA-β-gal activity, and senescence-associated heterochromatic foci (SAHF) formation. Under this condition, core histones and the linker histone H1 significantly decreased at both mRNA and protein levels, resulting in reduced nucleosome formation. Consistently, in activated Ras-induced senescent fibroblasts, the accumulation of MCAF1 in PML bodies was enhanced via the binding of this protein to SUMO molecules, suggesting that sequestration of MCAF1 to PML bodies promotes cellular senescence. Collectively, these results reveal that MCAF1 is an essential regulator of cellular senescence.