The histone variant macroH2A generally associates with transcriptionally inert chromatin; however, the factors that regulate its chromatin incorporation remain elusive. Here, we identify the SWI/SNF helicase ATRX (a-thalassemia/ MR, X-linked) as a novel macroH2A-interacting protein.Unlike its role in assisting H3.3 chromatin deposition, ATRX acts as a negative regulator of macroH2A's chromatin association. In human erythroleukemic cells deficient for ATRX, macroH2A accumulates at the HBA gene cluster on the subtelomere of chromosome 16, coinciding with the loss of a-globin expression. Collectively, our results implicate deregulation of macroH2A's distribution as a contributing factor to the a-thalassemia phenotype of ATRX syndrome. The replacement of canonical histones with histone variants contributes to the dynamic nature of chromatin.Due to amino acid differences and, in turn, unique posttranslational modifications, histone variants can alter nucleosome structure, stability, and binding of effector proteins. Histone variants have unique genomic localization patterns, and thus specialized roles such as regulating gene expression or chromosome segregation during cell division . Therefore, the differential genomic incorporation of histone variants directly impacts critical cellular functions.The histone variant macroH2A (mH2A) is a vertebratespecific member of the H2A family and is unusual due to the presence of a C-terminal macro domain (Pehrson and Fried 1992). Two different genes encode mH2A1 and mH2A2 (H2AFY and H2AFY2, respectively), and two splice forms of mH2A1 exist: mH2A1.1 and mH2A1.2 (Costanzi and Pehrson 2001). mH2A is abundant in heterochromatin, including senescence-associated heterochromatic foci (SAHF) and the inactivated X chromosome (Xi) (Costanzi and Pehrson 1998;Zhang et al. 2005). In vitro studies suggest that the macro domain sterically hinders access of transcription factors to DNA, while mH2A's L1 loop produces inflexible nucleosomes (Angelov et al. 2003;Chakravarthy et al. 2005).Our group has recently demonstrated a role for mH2A isoforms in suppressing melanoma progression, and others have linked mH2A expression or its splice patterns to breast and lung cancer (Sporn et al. 2009;Kapoor et al. 2010;Novikov et al. 2011). However, the factors that regulate the association of mH2A with chromatin remain obscure. Therefore, identifying regulators of the incorporation of histone variants at distinct genomic loci is key to understanding how chromatin domains are established and maintained and how these may go awry in disease.A second group of factors contributing to chromatin dynamics are ATP-dependent chromatin remodeling complexes that rearrange or mobilize nucleosomes. Deregulation of members of the SWI/SNF family is implicated in various cancers and mental retardation (MR) syndromes, including ATRX (a-thalassemia/MR, X-linked), (Wilson and Roberts 2011). Mutations in ATRX, predominantly found in the H3K9me3-binding ADD (ATRX-DNMT3-DNMT3L) and/or helicase domains, are associated with ATRX sy...

Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently upregulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways.